Marisa C. Kozlowski

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Name: Kozlowski, Marisa C.

Organization: University of Pennsylvania , USA

Department: Department of Chemistry

Title: Professor(PhD)

TOPICS

Organic Chemistry

Asymmetric Synthesis allene

Chemicals
References

Asymmetric Oxidative Coupling of Phenols and Hydroxycarbazoles

Co-reporter:Houng Kang, Young Eun Lee, Peddiahgari Vasu Govardhana Reddy, Sangeeta Dey, Scott E. Allen, Kyle A. Niederer, Paul Sung, Kirsten Hewitt, Carilyn Torruellas, Madison R. Herling, and Marisa C. Kozlowski

Organic Letters October 20, 2017 Volume 19(Issue 20) pp:5505-5505

Publication Date(Web):October 12, 2017

DOI:10.1021/acs.orglett.7b02552

The first examples of asymmetric oxidative coupling of simple phenols and 2-hydroxycarbazoles are outlined. Generation of a more vanadium catalyst by ligand design and by addition of an exogenous Brønsted or Lewis acid was found to be key to coupling the more oxidatively resistant phenols. The resultant vanadium complex is both more Lewis acidic and more strongly oxidizing. Good to excellent levels of enantioselectivity could be obtained, and simple trituration readily provided the products with ≥95% ee.

Catalytic Kinetic Resolution of Disubstituted Piperidines by Enantioselective Acylation: Synthetic Utility and Mechanistic Insights

Co-reporter:Benedikt Wanner; Imants Kreituss; Osvaldo Gutierrez; Marisa C. Kozlowski;Jeffrey W. Bode

Journal of the American Chemical Society 2015 Volume 137(Issue 35) pp:11491-11497

Publication Date(Web):August 26, 2015

DOI:10.1021/jacs.5b07201

The catalytic kinetic resolution of cyclic amines with achiral N-heterocyclic carbenes and chiral hydroxamic acids has emerged as a promising method to obtain enantio-enriched amines with high selectivity factors. In this report, we describe the catalytic kinetic resolution of disubstituted piperdines with practical selectivity factors (s, up to 52) in which we uncovered an unexpected and pronounced conformational effect resulting in disparate reactivity and selectivity between the cis- and trans-substituted piperidine isomers. Detailed experimental and computational studies of the kinetic resolution of various disubstituted piperidines revealed a strong preference for the acylation of conformers in which the α-substituent occupies the axial position. This work provides further experimental and computational support for the concerted 7-member transition state model for acyl transfer reagents and expands the scope and functional group tolerance of the secondary amine kinetic resolution.

Nickel-Catalyzed Cross-Coupling of Photoredox-Generated Radicals: Uncovering a General Manifold for Stereoconvergence in Nickel-Catalyzed Cross-Couplings

Co-reporter:Osvaldo Gutierrez; John C. Tellis; David N. Primer; Gary A. Molander

Journal of the American Chemical Society 2015 Volume 137(Issue 15) pp:4896-4899

Publication Date(Web):April 2, 2015

DOI:10.1021/ja513079r

The cross-coupling of sp3-hybridized organoboron reagents via photoredox/nickel dual catalysis represents a new paradigm of reactivity for engaging alkylmetallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using density functional theory. Calculations bring to light a new reaction pathway involving an alkylnickel(I) complex generated by addition of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism. Analysis of the enantioselective variant of the transformation reveals an unexpected manifold for stereoinduction involving dynamic kinetic resolution (DKR) of a Ni(III) intermediate wherein the stereodetermining step is reductive elimination. Furthermore, calculations suggest that the DKR-based stereoinduction manifold may be responsible for stereoselectivity observed in numerous other stereoconvergent Ni-catalyzed cross-couplings and reductive couplings.

Practical, Asymmetric Route to Sitagliptin and Derivatives: Development and Origin of Diastereoselectivity

Co-reporter:Osvaldo Gutierrez, Dattatray Metil, Namrata Dwivedi, Nagaraju Gudimalla, E. R. R. Chandrashekar, Vilas H. Dahanukar, Apurba Bhattacharya, Rakeshwar Bandichhor, and Marisa C. Kozlowski

Organic Letters 2015 Volume 17(Issue 7) pp:1742-1745

Publication Date(Web):March 23, 2015

DOI:10.1021/acs.orglett.5b00520

The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate S═O, consistent with MsOH being crucial for high selectivity. The second is a novel C–H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand.

Vanadium-Catalyzed Regioselective Oxidative Coupling of 2-Hydroxycarbazoles

Co-reporter:Lei Liu, Patrick J. Carroll, and Marisa C. Kozlowski

Organic Letters 2015 Volume 17(Issue 3) pp:508-511

Publication Date(Web):January 15, 2015

DOI:10.1021/ol503521b

The first regioselective oxidative coupling of 2-hydroxycarbazoles is described. With a vanadium catalyst and oxygen as the terminal oxidant, dimers with an ortho–ortho′ coupling pattern were obtained with high selectivity. Further oxidation led to ortho′–ortho′ coupling to generate a tetramer, which provided insight that the atropisomerization barriers of the unsymmetrical biaryl bonds are much lower than expected.

Palladium-Catalyzed α-Arylation of Aryl Nitromethanes

Co-reporter:Kelsey F. VanGelder and Marisa C. Kozlowski

Organic Letters 2015 Volume 17(Issue 23) pp:5748-5751

Publication Date(Web):November 20, 2015

DOI:10.1021/acs.orglett.5b02793

Catalytic conditions for the α-arylation of aryl nitromethanes have been discovered using parallel microscale experimentation, despite two prior reports of the lack of reactivity of these aryl nitromethane precursors. The method efficiently provides a variety of substituted, isolable diaryl nitromethanes. In addition, it is possible to sequentially append two different aryl groups to nitromethane. Mild oxidation conditions were identified to afford the corresponding benzophenones via the Nef reaction, and reduction conditions were optimized to afford several diaryl methylamines.

Xanthene-4,5-diamine derivatives: a study of anion-binding catalysis

Co-reporter:Alison E. Metz, Kailasham Ramalingam, Marisa C. Kozlowski

Tetrahedron Letters 2015 Volume 56(Issue 37) pp:5180-5184

Publication Date(Web):9 September 2015

DOI:10.1016/j.tetlet.2015.07.058

This study describes the synthesis of a class of anion-binding catalysts based on a xanthene scaffold. Both unsymmetrical catalysts and C2-symmetrical catalysts were generated, and were examined in the cyclization of 3- and 2-substituted furans onto N-acyliminium ions. Good conversion for each reaction was observed with a variety of anion-binding catalysts (42–76%).

Cinchonidinium acetate as a convenient catalyst for the asymmetric synthesis of cis-stilbenediamines

Co-reporter:Ryan R. Walvoord, Marisa C. Kozlowski

Tetrahedron Letters 2015 Volume 56(Issue 23) pp:3070-3074

Publication Date(Web):3 June 2015

DOI:10.1016/j.tetlet.2014.12.105

Inexpensive and readily available cinchonidinium acetate is an effective catalyst for the syn-selective aza-Henry reaction of arylnitromethanes and aryl imines. The resulting masked cis-stilbenediamine products are produced in excellent diastereoselectivity and good enantioselectivity, and enantiopure material can be achieved via recrystallization. The features of the cinchona catalyst needed for selectivity are discussed, with specific emphasis on formation of a kinetically controlled syn-product without epimerization of the highly acidic α-nitro stereocenter.

Route to α-Aryl Phosphonoacetates: Useful Synthetic Precursors in the Horner–Wadsworth–Emmons Olefination

Co-reporter:Kelsey F. VanGelder, Melinda Wang, and Marisa C. Kozlowski

The Journal of Organic Chemistry 2015 Volume 80(Issue 20) pp:10288-10293

Publication Date(Web):September 25, 2015

DOI:10.1021/acs.joc.5b01887

A versatile and general catalytic strategy has been developed for the α-arylation of phosphonoacetates utilizing parallel microscale experimentation. These α-substituted phosphonoacetates are widely useful, notably as substrates in the Horner–Wadsworth–Emmons-type olefinations. However, the current routes to these products involve harsh conditions, limiting the variety of functionality. The reported method can be used with a variety of aryl chlorides and aryl bromides, including several heterocyclic examples.

Recent Advances in Asymmetric Catalytic Methods for the Formation of Acyclic α,α-Disubstituted α-Amino Acids

Co-reporter:Alison E. Metz and Marisa C. Kozlowski

The Journal of Organic Chemistry 2015 Volume 80(Issue 1) pp:1-7

Publication Date(Web):November 28, 2014

DOI:10.1021/jo502408z

Because of their greater stability and unique conformational properties, unnatural amino acids are highly valued by pharmaceutical, biological, and organic chemists. This synopsis surveys the various catalytic methods used to access enantioenriched, acyclic α,α-disubstituted α-amino acids with a focus on the processes developed since 2007, when the last major reviews in this area were published.

Quantification of Electrophilic Activation by Hydrogen-Bonding Organocatalysts

Co-reporter:Ryan R. Walvoord ; Phuong N. H. Huynh

Journal of the American Chemical Society 2014 Volume 136(Issue 45) pp:16055-16065

Publication Date(Web):October 17, 2014

DOI:10.1021/ja5086244

A spectrophotometric sensor is described that provides a useful assessment of the LUMO-lowering provided by catalysts in Diels–Alder and Friedel–Crafts reactions. A broad range of 33 hydrogen-bonding catalysts was assessed with the sensor, and the relative rates in the above reactions spanned 5 orders of magnitude as determined via 1H- and 2H NMR spectroscopic measurements, respectively. The differences between the maximum wavelength shift of the sensor with and without catalyst (Δλmax–1) were found to correlate linearly with ln(krel) values for both reactions, even though the substrate feature that interacts with the catalyst differs significantly (ketone vs nitro). The sensor provides an assessment of both the inherent reactivity of a catalyst architecture as well as the sensitivity of the reaction to changes within an architecture. In contrast, catalyst pKa values are a poor measure of reactivity, although correlations have been identified within catalyst classes.

Chemoselective Activation of sp3 vs sp2 C–H Bonds with Pd(II)

Co-reporter:John M. Curto

Journal of the American Chemical Society 2014 Volume 137(Issue 1) pp:18-21

Publication Date(Web):November 25, 2014

DOI:10.1021/ja5093166

The first selective coupling of a carbon nucleophile with methyl, ethyl, propyl, and butyl arenes in the absence of a directing group is described. Pd(OAc)2 double C–H activation displays remarkable selectivity for the terminal methyl sites in alkyl arenes, rather than the more commonly observed arene sp2 C–H activation. Mechanistic studies indicate the intermediacy of an azlactone dimer, obtained from oxidation with Pd(OAc)2, and are consistent with a Pd-catalyzed C–H activation vs a radical process. The observed reactivity establishes that typical reaction solvents (e.g., toluene) can readily participate in C–H activation chemistry.

Axial Chiral Bisbenzophenazines: Solid-State Self-Assembly via Halide Hydrogen Bonds Triggered by Linear Alkanes

Co-reporter:Alison E. Metz ; Erin E. Podlesny ; Patrick J. Carroll ; Ariel N. Klinghoffer

Journal of the American Chemical Society 2014 Volume 136(Issue 30) pp:10601-10604

Publication Date(Web):July 14, 2014

DOI:10.1021/ja506137j

An axial chiral tetrachlorinated bisbenzo[a]phenazine has been discovered that undergoes an alkane-induced shift in the solid state from a disordered amorphous form to an ordered polycrystalline form. This phase transition is caused by the formation of pores that accommodate linear alkanes of varying lengths with a very strong affinity as judged by differential scanning calorimetry. Single crystal X-ray structure analysis revealed that a series of weak phenolic OH···Cl hydrogen bonds dictates the pore structure. These weak interactions can be disrupted mechanically, causing the material to revert to the amorphous form. Notably, the interchange between the amorphous and crystalline forms is readily reversible and is easily observed by characteristic colorimetric changes. Measurements via photoimage processing reveal that the degree of color change is dictated by the type of alkane employed.

Concerted Amidation of Activated Esters: Reaction Path and Origins of Selectivity in the Kinetic Resolution of Cyclic Amines via N-Heterocyclic Carbenes and Hydroxamic Acid Cocatalyzed Acyl Transfer

Co-reporter:Scott E. Allen ; Sheng-Ying Hsieh ; Osvaldo Gutierrez ; Jeffrey W. Bode

Journal of the American Chemical Society 2014 Volume 136(Issue 33) pp:11783-11791

Publication Date(Web):July 22, 2014

DOI:10.1021/ja505784w

The N-heterocyclic carbene and hydroxamic acid cocatalyzed kinetic resolution of cyclic amines generates enantioenriched amines and amides with selectivity factors up to 127. In this report, a quantum mechanical study of the reaction mechanism indicates that the selectivity-determining aminolysis step occurs via a novel concerted pathway in which the hydroxamic acid plays a key role in directing proton transfer from the incoming amine. This modality was found to be general in amide bond formation from a number of activated esters including those generated from HOBt and HOAt, reagents that are broadly used in peptide coupling. For the kinetic resolution, the proposed model accurately predicts the faster reacting enantiomer. A breakdown of the steric and electronic control elements shows that a gearing effect in the transition state is responsible for the observed selectivity.

Selective Oxidative Homo- and Cross-Coupling of Phenols with Aerobic Catalysts

Co-reporter:Young Eun Lee ; Trung Cao ; Carilyn Torruellas

Journal of the American Chemical Society 2014 Volume 136(Issue 19) pp:6782-6785

Publication Date(Web):May 5, 2014

DOI:10.1021/ja500183z

Simple catalysts that use atom-economical oxygen as the terminal oxidant to accomplish selective ortho–ortho, ortho–para, or para–para homo-couplings of phenols are described. In addition, chromium salen catalysts have been discovered as uniquely effective in the cross-coupling of different phenols with high chemo- and regioselectivity.

Asymmetric Synthesis of α-Allyl-α-Aryl α-Amino Acids by Tandem Alkylation/π-Allylation of α-Iminoesters

Co-reporter:John M. Curto, Joshua S. Dickstein, Simon Berritt, and Marisa C. Kozlowski

Organic Letters 2014 Volume 16(Issue 7) pp:1948-1951

Publication Date(Web):March 25, 2014

DOI:10.1021/ol500506t

The first asymmetric synthesis of α-allyl-α-aryl α-amino acids by means of a three-component coupling of α-iminoesters, Grignard reagents, and cinnamyl acetate is reported. Notably, the enolate from the tandem process provides a much higher level of reactivity and selectivity than the same enolate generated via direct deprotonation, presumably due to differences in the solvation/aggregation state. A novel method for removal of a homoallylic amine protecting group delivers the free amine congeners. The α-allyl group offers a means to generate further valuable α-amino acid structures as exemplified by ring closing metathesis to generate a higher ring homologue of α-aryl-proline.

Alkenes as Chelating Groups in Diastereoselective Additions of Organometallics to Ketones

Co-reporter:Ludovic Raffier, Osvaldo Gutierrez, Gretchen R. Stanton, Marisa C. Kozlowski, and Patrick J. Walsh

Organometallics 2014 Volume 33(Issue 19) pp:5371-5377

Publication Date(Web):September 9, 2014

DOI:10.1021/om5007006

Alkenes have been discovered to be chelating groups to Zn(II), enforcing highly stereoselective additions of organozincs to β,γ-unsaturated ketones. 1H NMR studies and DFT calculations provide support for this surprising chelation mode. The results expand the range of coordinating groups for chelation-controlled carbonyl additions from heteroatom Lewis bases to simple C–C double bonds, broadening the 60 year old paradigm.

α-Allyl-α-aryl α-Amino Esters in the Asymmetric Synthesis of Acyclic and Cyclic Amino Acid Derivatives by Alkene Metathesis

Co-reporter:John M. Curto and Marisa C. Kozlowski

The Journal of Organic Chemistry 2014 Volume 79(Issue 11) pp:5359-5364

Publication Date(Web):May 14, 2014

DOI:10.1021/jo500707t

Allylating agents were explored for the asymmetric synthesis of α-allyl-α-aryl α-amino acids by tandem N-alkylation/π-allylation. Cross-metathesis of the tandem product was developed to provide allylic diversity not afforded in the parent reaction; the synthesis of homotyrosine and homoglutamate analogues was completed. Cyclic α-amino acid derivatives could be accessed by ring-closing metathesis presenting a viable strategy to higher ring homologue of enantioenriched α-substituted proline. The eight-membered proline analogue was successfully converted to the pyrrolizidine natural product backbone.

Aerobic Copper-Catalyzed Organic Reactions

Co-reporter:Scott E. Allen, Ryan R. Walvoord, Rosaura Padilla-Salinas, and Marisa C. Kozlowski

Chemical Reviews 2013 Volume 113(Issue 8) pp:6234

Publication Date(Web):June 20, 2013

DOI:10.1021/cr300527g

Nitroethylation of Vinyl Triflates and Bromides

Co-reporter:Rosaura Padilla-Salinas, Ryan R. Walvoord, Sergei Tcyrulnikov, and Marisa C. Kozlowski

Organic Letters 2013 Volume 15(Issue 15) pp:3966-3969

Publication Date(Web):July 25, 2013

DOI:10.1021/ol401747u

A two-carbon homologation of vinyl triflates and bromides for the synthesis of homoallylic nitro products is described. This palladium-catalyzed double coupling of nitromethane exploits the anion stabilizing and leaving group properties of nitromethane, generating the homo allyl nitro products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides.

2-Aryl-2-nitroacetates as Central Precursors to Aryl Nitromethanes, α-Ketoesters, and α-Amino Acids

Co-reporter:Alison E. Metz and Marisa C. Kozlowski

The Journal of Organic Chemistry 2013 Volume 78(Issue 2) pp:717-722

Publication Date(Web):December 17, 2012

DOI:10.1021/jo302071s

Nitroarylacetates are useful small molecular building blocks that act as precursors to α-ketoesters and aryl nitromethanes as well as α-amino acids. Methods were developed that produce each of these compound types in good yields. Two different conditions for decarboxylation are discussed for substrates with neutral and electron-poor aryl groups versus electron-rich aryl groups. For formation of the α-ketoesters, new mild conditions for the Nef disproportionation were identified.

Divergent Approach to the Bisanthraquinone Natural Products: Total Synthesis of (S)-Bisoranjidiol and Derivatives from Binaphtho-para-quinones

Co-reporter:Erin E. Podlesny and Marisa C. Kozlowski

The Journal of Organic Chemistry 2013 Volume 78(Issue 2) pp:466-476

Publication Date(Web):December 18, 2012

DOI:10.1021/jo302364h

The development of the first asymmetric synthesis of a chiral anthraquinone dimer is outlined, resulting in the first total synthesis of (S)-bisoranjidiol. Rather than a biomimetic dimerization retrosynthetic disconnection, the anthracenyl ring systems are generated after formation of the axially chiral binaphthalene framework. This synthetic strategy has enabled the synthesis of several analogues. Key features of the synthesis include the enantioselective coupling of a hindered 2-naphthol containing substitution peri to the site of C–C bond formation, the regioselective oxidation of 8,8′-hydroxylated binaphthols to binaphtho-para-quinones, and a tandem regioselective Diels–Alder/aromatization reaction.

Mild Aromatic Palladium-Catalyzed Protodecarboxylation: Kinetic Assessment of the Decarboxylative Palladation and the Protodepalladation Steps

Co-reporter:Joshua S. Dickstein, John M. Curto, Osvaldo Gutierrez, Carol A. Mulrooney, and Marisa C. Kozlowski

The Journal of Organic Chemistry 2013 Volume 78(Issue 10) pp:4744-4761

Publication Date(Web):April 16, 2013

DOI:10.1021/jo400222c

Mechanism studies of a mild palladium-catalyzed decarboxylation of aromatic carboxylic acids are described. In particular, reaction orders and activation parameters for the two stages of the transformation were determined. These studies guided development of a catalytic system capable of turnover. Further evidence reinforces that the second stage, protonation of the arylpalladium intermediate, is the rate-determining step of the reaction. The first step, decarboxylative palladation, is proposed to occur through an intramolecular electrophilic palladation pathway, which is supported by computational and mechanism studies. In contrast to the reverse reaction (C–H insertion), the data support an electrophilic aromatic substitution mechanism involving a stepwise intramolecular protonation sequence for the protodepalladation portion of the reaction.

Minimizing the Amount of Nitromethane in Palladium-Catalyzed Cross-Coupling with Aryl Halides

Co-reporter:Ryan R. Walvoord and Marisa C. Kozlowski

The Journal of Organic Chemistry 2013 Volume 78(Issue 17) pp:8859-8864

Publication Date(Web):July 30, 2013

DOI:10.1021/jo401249y

A method for the formation of arylnitromethanes is described that employs readily available aryl halides or triflates and small amounts of nitromethane in a dioxane solvent, thereby reducing the hazards associated with this reagent. Specifically, 2–10 equiv (1–5% v/v) of nitromethane can be employed in comparison to prior work that used nitromethane as solvent (185 equiv). The present transformation provides high yields at relatively low temperatures and tolerates an array of functionality, including heterocycles and substantial steric encumbrance.

Rapid Quantification of the Activating Effects of Hydrogen-Bonding Catalysts with a Colorimetric Sensor

Co-reporter:Phuong N. H. Huynh ; Ryan R. Walvoord

Journal of the American Chemical Society 2012 Volume 134(Issue 38) pp:15621-15623

Publication Date(Web):September 13, 2012

DOI:10.1021/ja3050663

A sensor has been developed to quickly and simply assess the relative reactivity of different hydrogen-bonding catalysts. Specifically, blue-shifts seen upon treatment of H-bonding catalysts with the colorimetric compound 7-methyl-2-phenylimidazo[1,2-a]pyrazin-3(7H)-one correlate well to the Keq of binding to the sensor. The blue-shifts also show a high degree of correlation with relative rates in Diels–Alder reactions of methyl vinyl ketone and cyclopentadiene employing the H-bonding catalysts. The relevance of the sensor blue-shifts to the LUMO-lowering abilities of the H-bonding catalysts is discussed.

Oxyanion Steering and CH−π Interactions as Key Elements in an N-Heterocyclic Carbene-Catalyzed [4 + 2] Cycloaddition

Co-reporter:Scott E. Allen ; Jessada Mahatthananchai ; Jeffrey W. Bode

Journal of the American Chemical Society 2012 Volume 134(Issue 29) pp:12098-12103

Publication Date(Web):July 4, 2012

DOI:10.1021/ja302761d

The N-heterocyclic carbene catalyzed [4 + 2] cycloaddition has been shown to give γ,δ-unsaturated δ-lactones in excellent enantio- and diastereoselectivity. However, preliminary computational studies of the geometry of the intermediate enolate rendered ambiguous both the origins of selectivity and the reaction pathway. Here, we show that a concerted, but highly asynchronous, Diels–Alder reaction occurs rather than the stepwise Michael-type or Claisen-type pathways. In addition, two crucial interactions are identified that enable high selectivity: an oxyanion-steering mechanism and a CH−π interaction. The calculations accurately predict the enantioselectivity of a number of N-heterocyclic carbene catalysts in the hetero-Diels–Alder reaction.

Palladium-Catalyzed Nitromethylation of Aryl Halides: An Orthogonal Formylation Equivalent

Co-reporter:Ryan R. Walvoord, Simon Berritt, and Marisa C. Kozlowski

Organic Letters 2012 Volume 14(Issue 16) pp:4086-4089

Publication Date(Web):July 27, 2012

DOI:10.1021/ol301713j

An efficient cross-coupling reaction of aryl halides and nitromethane was developed with the use of parallel microscale experimentation. The arylnitromethane products are precursors for numerous useful synthetic products. An efficient method for their direct conversion to the corresponding oximes and aldehydes in a one-pot operation has been discovered. The process exploits inexpensive nitromethane as a carbonyl equivalent, providing a mild and convenient formylation method that is compatible with many functional groups.

Selective Oxidation of 8,8′-Hydroxylated Binaphthols to Bis-spironaphthalenones or Binaphtho-para- and Binaphtho-ortho-quinones

Co-reporter:Erin E. Podlesny, Patrick J. Carroll, and Marisa C. Kozlowski

Organic Letters 2012 Volume 14(Issue 18) pp:4862-4865

Publication Date(Web):August 31, 2012

DOI:10.1021/ol302195e

The selective oxidation of a series of functionalized 8,8′-hydroxylated binaphthols to binaphtho-para- and binaphtho-ortho-quinones has been realized using either a Co-salen catalyst or ortho-iodoxybenzoic acid. A unique spirocyclic bis-spironaphthalenone was also obtained in good yield via a phenyliodonium diacetate promoted oxidative dearomatization.

Efficient Palladium-Catalyzed Cross-Coupling of Highly Acidic Substrates, Nitroacetates

Co-reporter:Alison E. Metz, Simon Berritt, Spencer D. Dreher, and Marisa C. Kozlowski

Organic Letters 2012 Volume 14(Issue 3) pp:760-763

Publication Date(Web):January 20, 2012

DOI:10.1021/ol203303b

Palladium-catalyzed cross-coupling conditions were developed that efficiently afford 2-aryl-2-nitroacetates from aryl bromides and the very acidic nitroacetates.

Structural Reassignment of a Marine Metabolite from a Binaphthalenetetrol to a Tetrabrominated Diphenyl Ether

Co-reporter:Erin E. Podlesny

Journal of Natural Products 2012 Volume 75(Issue 6) pp:1125-1129

Publication Date(Web):June 12, 2012

DOI:10.1021/np300141t

The structure of a reported natural product isolate has been revised from (S)-2,2′-dimethoxy-[1,1′-binaphthalene]-5,5′,6,6′-tetraol to a known tetrabrominated diphenyl ether. After total synthesis of the reported binaphthalenetetrol was accomplished via a key reduction of a binaphtho-ortho-quinone, comparison of the physical properties and NMR spectroscopic data of the synthetic material indicated that the structure of the natural product isolate was incorrect. Evaluation of the authentic natural product suggested the structure is a tetrabrominated diphenyl ether, likely 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol.

Perylenequinones: Isolation, Synthesis, and Biological Activity

Co-reporter:Carol A. Mulrooney;Erin M. O'Brien;Barbara J. Morgan

European Journal of Organic Chemistry 2012 Volume 2012( Issue 21) pp:3887-3904

Publication Date(Web):

DOI:10.1002/ejoc.201200184

Abstract

The perylenequinones are a class of natural products characterized by a pentacyclic conjugated chromophore giving rise to photoactivity. Potentially useful light-activated biological activity, targeting protein kinase C (PKC), has been identified for several of the natural products. Recently discovered new members of this compound class, as well as several related phenanthro-perylenequinones, are reviewed. Natural product modifications that improve biological profiles are outlined, as well as avenues for the total synthesis of analogs not available from the natural product series. An overview of structure/function relationships is provided.

Asymmetric Synthesis of Allenyl Oxindoles and Spirooxindoles by a Catalytic Enantioselective SaucyMarbet Claisen Rearrangement

Co-reporter:Trung Cao;Joshua Deitch;Dr. Elizabeth C. Linton ; Marisa C. Kozlowski

Angewandte Chemie International Edition 2012 Volume 51( Issue 10) pp:2448-2451

Publication Date(Web):

DOI:10.1002/anie.201107417

Copper(II)- and Palladium(II)-Catalyzed Enantioselective Claisen Rearrangement of Allyloxy- and Propargyloxy-Indoles to Quaternary Oxindoles and Spirocyclic Lactones

Co-reporter:Trung Cao, Elizabeth C. Linton, Joshua Deitch, Simon Berritt, and Marisa C. Kozlowski

The Journal of Organic Chemistry 2012 Volume 77(Issue 24) pp:11034-11055

Publication Date(Web):November 20, 2012

DOI:10.1021/jo302039n

In this Article, a strategy to obtain highly enantioselective catalysts for the Claisen rearrangement of allyloxy- and propargyloxy-indoles is outlined. Ultimately, copper BOX and palladium BINAP or PHOX catalysts were discovered as superior in catalyzing Claisen rearrangements of allyloxy- or proparyloxy-substituted indoles to generate oxindoles bearing allyl- or allenyl-substituted quaternary centers. This method proved to be tolerant of a broad range of functional groups. Tandem reactions of the silyl-allene products provide rapid access to a variety of spirocyclic oxindoles in one operation.

Asymmetric Synthesis of Allenyl Oxindoles and Spirooxindoles by a Catalytic Enantioselective SaucyMarbet Claisen Rearrangement

Co-reporter:Trung Cao;Joshua Deitch;Dr. Elizabeth C. Linton ; Marisa C. Kozlowski

Angewandte Chemie 2012 Volume 124( Issue 10) pp:2498-2501

Publication Date(Web):

DOI:10.1002/ange.201107417

Alternative Spiroketalization Methods toward Purpuromycin: A Hemiketal Conjugate Addition Strategy and Use of an Electron-Rich Isocoumarin Precursor

Co-reporter:Rakeshwar Bandichhor, Andrew N. Lowell, and Marisa C. Kozlowski

The Journal of Organic Chemistry 2011 Volume 76(Issue 16) pp:6475-6487

Publication Date(Web):June 27, 2011

DOI:10.1021/jo200398v

Two methods are presented that were designed to circumvent the persistent problem of benzofuran formation and instead yield a spiroketal of the rubromycin family type. First, using an alternative disconnection, a hemiketal conjugate addition to a naphthaquinone electrophile was investigated. Synthesis of the requisite electrophile provided insight into the selective oxidation and functionalization of the naphthalene portion. Second, the electronic features of the isocoumarin ring system were adjusted, and the corresponding reactivity further supports the hypothesis that electron-rich isocoumarins are capable of spiroketalization. Robust, flexible syntheses from simple precursors were developed that allowed multiple reduced isocoumarins to be generated. Combined, the data presented herein give insight into the sensitivities of this family and illuminate other potential methods of spiroketalization. In addition, the convergent assembly of substrates containing different naphthaquinone and isocoumarin subunits highlights the utility of our 1,3-dipolar cycloaddition approach to generate analogs of these structures for SAR, as well as chemical reactivity studies.

Alternative Spiroketalization Methods toward Purpuromycin: A Diketone Approach To Prevent Benzofuran Formation

Co-reporter:Andrew N. Lowell, Michael W. Fennie, and Marisa C. Kozlowski

The Journal of Organic Chemistry 2011 Volume 76(Issue 16) pp:6488-6502

Publication Date(Web):June 27, 2011

DOI:10.1021/jo200399z

The central portion of purpuromycin has been assembled via a classical spiroketalization reaction. Key to promoting this reaction mode versus benzofuran formation was the oxidation state of the spiroketal core. With a higher oxidation state, even the electron-deficient isocoumarin found in purpuromycin could be employed directly in the spiroketalization. The two halves of the spiroketalization precursor were joined via a nitrile oxide/styrene 1,3-dipolar cycloaddition. A very mild selenium dioxide oxidation was used to introduce the required oxidation state of the spiroketal core.

Syntheses of differentially protected isocoumarins

Co-reporter:Andrew N. Lowell, Philip D. Wall, Stephen P. Waters, Marisa C. Kozlowski

Tetrahedron 2010 66(30) pp: 5573-5582

Publication Date(Web):

DOI:10.1016/j.tet.2010.05.077

Quantum molecular interaction field models of substrate enantioselection in asymmetric processes

Co-reporter:Marisa C. Kozlowski, James C. Ianni

Journal of Molecular Catalysis A: Chemical 2010 324(1–2) pp: 141-145

Publication Date(Web):

DOI:10.1016/j.molcata.2010.03.030

Perylenequinone Natural Products: Evolution of the Total Synthesis of Cercosporin

Co-reporter:Barbara J. Morgan, Carol A. Mulrooney and Marisa C. Kozlowski

The Journal of Organic Chemistry 2010 Volume 75(Issue 1) pp:44-56

Publication Date(Web):November 9, 2009

DOI:10.1021/jo9013854

The evolution of the first total synthesis of perylenequinone cercosporin is described. The key features developed during these efforts include a biscuprate epoxide alkylation, installation of the methylidene acetal, palladium-catalyzed O-arylation, and C3,C3′-decarbonylation. Due to the rapid atropisomerization of the helical axis of cercosporin (at 37 °C), the sequencing of these transformations was critical. To this end, the developed protocol enabled the formation of a key advanced intermediate on preparative scale absent any atropisomerization. Furthermore, the O-arylation proved to be general, and the strategy was used in an improved synthesis of a helical chiral perylenequinone structure.

Total synthesis of chiral biaryl natural products by asymmetric biaryl coupling

Co-reporter:Marisa C. Kozlowski, Barbara J. Morgan and Elizabeth C. Linton

Chemical Society Reviews 2009 vol. 38(Issue 11) pp:3193-3207

Publication Date(Web):23 Sep 2009

DOI:10.1039/B821092F

This tutorial review highlights the use of catalytic asymmetric 2-naphthol couplings in total synthesis. The types of chirality, chiral biaryl natural products, prior approaches to chiral biaryl natural products, and other catalytic asymmetric biaryl couplings are outlined. The three main categories of chiral catalysts for 2-naphthol coupling (Cu, V, Fe) are described with discussion of their limitations and advantages. Applications of the copper catalyzed couplings in biomimetic syntheses are discussed including nigerone, hypocrellin, calphostin D, phleichrome, and cercosporin.

Design, Synthesis, and Investigation of Protein Kinase C Inhibitors: Total Syntheses of (+)-Calphostin D, (+)-Phleichrome, Cercosporin, and New Photoactive Perylenequinones

Co-reporter:Barbara J. Morgan ; Sangeeta Dey ; Steven W. Johnson

Journal of the American Chemical Society 2009 Volume 131(Issue 26) pp:9413-9425

Publication Date(Web):June 2, 2009

DOI:10.1021/ja902324j

The total syntheses of the PKC inhibitors (+)-calphostin D, (+)-phleichrome, cercosporin, and 10 novel perylenequinones are detailed. The highly convergent and flexible strategy developed employed an enantioselective oxidative biaryl coupling and a double cuprate epoxide opening, allowing the selective syntheses of all the possible stereoisomers in pure form. In addition, this strategy permitted rapid access to a broad range of analogues, including those not accessible from the natural products. These compounds provided a powerful means for evaluation of the perylenequinone structural features necessary to PKC activity. Simpler analogues were discovered with superior PKC inhibitory properties and superior photopotentiation in cancer cell lines relative to the more complex natural products.

Copper-Catalyzed N-Arylation of Hindered Substrates Under Mild Conditions

Co-reporter:MichaelT. Wentzel;J. Brian Hewgley;RajeshM. Kamble;PhilipD. Wall ;MarisaC. Kozlowski

Advanced Synthesis & Catalysis 2009 Volume 351( Issue 6) pp:931-937

Publication Date(Web):

DOI:10.1002/adsc.200800730

Organometal additions to α-iminoesters: N-alkylationvia umpolung

Co-reporter:Joshua S. Dickstein and Marisa C. Kozlowski

Chemical Society Reviews 2008 vol. 37(Issue 6) pp:1166-1173

Publication Date(Web):01 Apr 2008

DOI:10.1039/B709139G

α-Iminoesters are useful precursors to substituted α-amino acid derivatives and are utilized in a number of organic transformations. As a consequence of the adjacent ester functionality, these imines are more reactive relative to other types of imines. While a significant body of work has focused on nucleophilic additions to the imine carbon (C-alkylation), a second pathway that involves nucleophilic reaction at the nitrogen (N-alkylation) is much less explored. This tutorial review highlights work that has exploited this unusual α-iminoester reactivity mode.

Asymmetric Total Synthesis of Nigerone and ent-Nigerone: Enantioselective Oxidative Biaryl Coupling of Highly Hindered Naphthols

Co-reporter:Marisa C. Kozlowski;Elizabeth C. Dugan;Evan S. DiVirgilio;Katja Maksimenka;Gerhard Bringmann

Advanced Synthesis & Catalysis 2007 Volume 349(Issue 4-5) pp:

Publication Date(Web):20 MAR 2007

DOI:10.1002/adsc.200600570

An enantioselective synthesis of the chiral bisnaphthopyrone natural product nigerone and its enantiomer, ent-nigerone, has been realized. The use of constrained 2-naphthol substrates was critical to producing highly functionalized chiral 1,1′-binaphthols via asymmetric oxidative biaryl coupling with 1,5-diaza-cis-decalin copper complexes. The final natural product was formed via a key eight-step isomerization process of the coupling product, bisisonigerone, and proceeded with retention of the biaryl configuration. The axial configurations of bisisonigerone and nigerone were definitively established by a combination of circular dichroism (CD) measurements and quantum chemical CD calculations.

A Priori Theoretical Prediction of Selectivity in Asymmetric Catalysis: Design of Chiral Catalysts by Using Quantum Molecular Interaction Fields

Co-reporter:James C. Ianni Dr.;Venkatachalam Annamalai;Puay-Wah Phuan Dr.;Manoranjan Pa Dr. and

Angewandte Chemie 2006 Volume 118(Issue 33) pp:

Publication Date(Web):11 AUG 2006

DOI:10.1002/ange.200600329

Exzellente Vorhersage: Die Selektivitäten eines Satzes chiraler Katalysatoren wurden mit Methoden vorhergesagt, die von quantenmechanischen Feldern für molekulare Wechselwirkungen abgeleitet sind und auf Grundzustands- statt auf Übergangszustandsstrukturen angewendet wurden. Die Vorhersagen für die asymmetrische Addition von Et₂Zn an PhCHO stimmen bemerkenswert gut mit den experimentellen Daten überein (=0.87).

A Priori Theoretical Prediction of Selectivity in Asymmetric Catalysis: Design of Chiral Catalysts by Using Quantum Molecular Interaction Fields

Co-reporter:James C. Ianni Dr.;Venkatachalam Annamalai;Puay-Wah Phuan Dr.;Manoranjan Pa Dr. and

Angewandte Chemie International Edition 2006 Volume 45(Issue 33) pp:

Publication Date(Web):11 AUG 2006

DOI:10.1002/anie.200600329

Excellent forecast: The selectivities for a set of chiral catalysts were predicted by methods derived from quantum mechanical molecular interaction fields that were applied to ground-state structures rather than transition-state structures. The predictions for the asymmetric addition of Et₂Zn to PhCHO are in remarkable agreement with the experimental results (=0.87).

Oxidation of chiral α-phenylacetate derivatives: formation of dimers with contiguous quaternary stereocenters versus tertiary alcohols

Co-reporter:Marisa C. Kozlowski, Evan S. DiVirgilio, Krishnan Malolanarasimhan, Carol A. Mulrooney

Tetrahedron: Asymmetry 2005 Volume 16(Issue 21) pp:3599-3605

Publication Date(Web):31 October 2005

DOI:10.1016/j.tetasy.2005.10.008

The menthol esters of α-phenylacetate derivatives undergo diastereoselective oxidative dimerizations (α-cyano) in the presence of oxidants, and nitrosylation (α-amido) in the presence of CAN to form products containing adjacent functionalized quaternary stereocenters and tertiary alcohols, respectively.(2R,3S)-Bis(2-isopropyl-5-methylcyclohexyl) 2,3-dicyano-2,3-diphenylsuccinateC38H48N2O4[α]D23=-45.1 (c 0.61, CHCl3)(2R,3S)-Bis(2-isopropyl-5-methylcyclohexyl) 2,3-dicyano-2,3-dip-tolylsuccinateC40H52N2O4[α]D23=-50.2 (c 0.96, CHCl3)(2S,3S)-Bis(2-isopropyl-5-methylcyclohexyl) 2,3-dicyano-2,3-dip-tolylsuccinateC40H52N2O4[α]D23=-148.5 (c 0.90, CHCl3)(2S)-2-Isopropyl-5-methylcyclohexyl 3-amino-2-hydroxy-3-oxo-2-phenylpropanoateC19H27NO4[α]D23=-88.7 (c 0.62, CHCl3)(5S)-2-Isopropyl-5-methylcyclohexyl 2,2-dimethyl-4-oxo-5-phenyloxazolidine-5-carboxylateC22H31NO4[α]D23=-53.4 (c 0.72, CHCl3)(R)-2,3-Dihydroxy-N-isopropyl-2-phenylpropanamideC12H17NO3[α]D23=+3.5 (c 0.38, CHCl3)

Novel Pathways for the Formation of Chiral Binaphthyl Polymers: Oxidative Asymmetric Phenolic Coupling Alone and in Tandem with the Glaser–Hay Coupling

Co-reporter:Xu Xie;Puay-Wah Phuan

Angewandte Chemie 2003 Volume 115(Issue 19) pp:

Publication Date(Web):14 MAY 2003

DOI:10.1002/ange.200250325

Einfach, aber gut geordnet! Durch eine Folge von zwei unterschiedlichen Kupplungreaktionen können aus Alkinylnaphtholen mit hoher Stereoselektivität chirale Binaphthyl-Polymere erhalten werden (siehe Bild). Die bemerkenswerte Chemoselektivität der Kupplungsschritte ermöglicht den gezielten Aufbau funktionalisierter Produkte in einer Eintopfreaktion.

Novel Pathways for the Formation of Chiral Binaphthyl Polymers: Oxidative Asymmetric Phenolic Coupling Alone and in Tandem with the Glaser–Hay Coupling

Co-reporter:Xu Xie;Puay-Wah Phuan

Angewandte Chemie International Edition 2003 Volume 42(Issue 19) pp:

Publication Date(Web):14 MAY 2003

DOI:10.1002/anie.200250325

Unusually orderly! Alkynylnaphthols undergo two kinds of couplings stepwise, with high stereocontrol, and in one pot to give chiral binaphthyl polymers like that shown. Since the chemoselectivity of each coupling is remarkably high, this approach is useful for the organized assembly of multifunctional substrates in a single operation.

Utility of calculated 13C NMR chemical shifts in differentiating conformational isomers: a study of metal-complexed and uncomplexed bispidines

Co-reporter:Manoranjan Panda, Puay-Wah Phuan and Marisa C. Kozlowski

Chemical Communications 2002 (Issue 14) pp:1552-1553

Publication Date(Web):19 Jun 2002

DOI:10.1039/B201950G

Calculated 13C NMR chemical shifts were key to assigning the structures of the conformational forms of complexed and uncomplexed bispidine derivatives

Enantioselective Total Synthesis of (S)-Bisoranjidiol, an Axially Chiral Bisanthraquinone

Co-reporter:Erin E. Podlesny

Organic Letters () pp:

Publication Date(Web):February 24, 2012

DOI:10.1021/ol3001365

The first enantioselective total synthesis of the bisanthraquinone (S)-bisoranjidiol and an unnatural regioisomer has been accomplished. Key features of the synthesis include the asymmetric oxidative biaryl coupling of a hindered 8-substituted 2-naphthol, selective para-quinone formation, and regioselective tandem Diels–Alder/aromatization reactions.

Organometal additions to α-iminoesters: N-alkylationvia umpolung

Co-reporter:Joshua S. Dickstein and Marisa C. Kozlowski

Chemical Society Reviews 2008 - vol. 37(Issue 6) pp:NaN1173-1173

Publication Date(Web):2008/04/01

DOI:10.1039/B709139G

Total synthesis of chiral biaryl natural products by asymmetric biaryl coupling

Co-reporter:Marisa C. Kozlowski, Barbara J. Morgan and Elizabeth C. Linton

Chemical Society Reviews 2009 - vol. 38(Issue 11) pp:NaN3207-3207

Publication Date(Web):2009/09/23

DOI:10.1039/B821092F