Alison J. Frontier

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Name: Frontier, Alison J.

Organization: University of Rochester , USA

Department: Department of Chemistry

Title: Professor(PhD)

TOPICS

Organic Chemistry

allene

Chemicals
References

Nazarov Cyclization/Internal Redox Cyclization Sequence for the Synthesis of N-Heterocyclic Bridged Ring Systems

Co-reporter:Yu-Wen Huang and Alison J. Frontier

Organic Letters 2016 Volume 18(Issue 19) pp:4896-4899

Publication Date(Web):September 21, 2016

DOI:10.1021/acs.orglett.6b02369

A 1,6 conjugate addition/Nazarov electrocyclization/internal redox cyclization sequence was developed. Various 5-hydroxycyclopentenones were made through the 1,6-conjugate addition initiated Nazarov reaction with excellent diastereoselectivities. Under thermal conditions, these underwent a through-space 1,5-hydride-transfer/ring-closure reaction to form bridged bicyclic N-heterocyclic compounds with up to four stereogenic centers. It was also possible to convert simple acyclic dienyl diketones into the bicyclo[3.2.1] products in a one-pot process (with a solvent switch).

Studies toward the AB ring system of the tetrapetalone natural products

Co-reporter:Peter N. Carlsen, Chao Jiang, Ildiko R. Herrick, Alison J. Frontier

Tetrahedron 2015 Volume 71(Issue 35) pp:5886-5896

Publication Date(Web):2 September 2015

DOI:10.1016/j.tet.2015.05.021

Synthetic efforts toward the rapid assembly of the AB ring system of the tetrapetalones is described. Key to this work was the use of [3+2] cycloaddition/oxidative extrusion methodology to furnish functionalized aryl enones. The Nazarov cyclization of these substrates was examined, and optimized to generate the AB ring carbon skeleton. Then, Pd-catalyzed cross-coupling were conducted, and conditions were identified that enabled installatiion of the requisite C14–N bond.

Cationic Cyclizations and Rearrangements Promoted by a Heterogeneous Gold Catalyst

Co-reporter:Tulaza Vaidya, Ryan Cheng, Peter N. Carlsen, Alison J. Frontier, and Richard Eisenberg

Organic Letters 2014 Volume 16(Issue 3) pp:800-803

Publication Date(Web):January 16, 2014

DOI:10.1021/ol403542k

A heterogeneous gold catalyst with remarkable activity for promoting the electrophilic reactions of aryl vinyl ketones and aryl dienyl ketones is described. The catalyst is easy to prepare, is robust, and can be recycled. Low loadings are effective for different types of cationic reactions, including Nazarov cyclizations, lactonizations, and [1,2] shifts.

Synthesis of ()-TetrapetaloneA-Me Aglycon

Co-reporter:Peter N. Carlsen;Tyler J. Mann; Amir H. Hoveyda; Alison J. Frontier

Angewandte Chemie International Edition 2014 Volume 53( Issue 35) pp:9334-9338

Publication Date(Web):

DOI:10.1002/anie.201404410

Abstract

The first synthesis of (±)-tetrapetalone A-Me aglycon is described. Key bond-forming reactions include Nazarov cyclization, a ring-closing metathesis promoted with complete diastereoselectivity by a chiral molybdenum-based complex, tandem conjugate reduction/intramolecular aldol cyclization, and oxidative dearomatization.

No Acid Required: 4π and 6π Electrocyclization Reactions of Dienyl Diketones for the Synthesis of Cyclopentenones and 2H-Pyrans

Co-reporter:Steven D. Jacob, Joshua L. Brooks, and Alison J. Frontier

The Journal of Organic Chemistry 2014 Volume 79(Issue 21) pp:10296-10302

Publication Date(Web):October 17, 2014

DOI:10.1021/jo501914w

The 1,6-conjugate addition of nucleophiles to dienyl diketones produces either cyclopentenone or 2H-pyran products with high selectivity through either Nazarov (4π) or 6π electrocyclization, respectively. The outcome of the reaction is dependent upon the nature of the nucleophile used. Nucleophiles that are anionic or easily deprotonated exclusively produce cyclopentenones via Nazarov cyclization, whereas the neutral nucleophile DABCO promotes 6π cyclization to afford 2H-pyrans. Experimental evidence is presented for both retro-4π and -6π electrocyclization in these systems, lending support to the bifurcated mechanistic hypothesis proposed for these cyclizations.

Synthesis of ()-TetrapetaloneA-Me Aglycon

Co-reporter:Peter N. Carlsen;Tyler J. Mann; Amir H. Hoveyda; Alison J. Frontier

Angewandte Chemie 2014 Volume 126( Issue 35) pp:9488-9492

Publication Date(Web):

DOI:10.1002/ange.201404410

Abstract

Gold(III) Chloride-Catalyzed 6-endo-trig Oxa-Michael Addition Reactions for Diastereoselective Synthesis of Fused Tetrahydropyranones

Co-reporter:Jennifer Ciesielski;David Lebœuf;Harry A. Stern

Advanced Synthesis & Catalysis 2013 Volume 355( Issue 10) pp:2077-2082

Publication Date(Web):

DOI:10.1002/adsc.201300265

Beyond the Divinyl Ketone: Innovations in the Generation and Nazarov Cyclization of Pentadienyl Cation Intermediates

Co-reporter:William T. Spencer III;Tulaza Vaidya

European Journal of Organic Chemistry 2013 Volume 2013( Issue 18) pp:3621-3633

Publication Date(Web):

DOI:10.1002/ejoc.201300134

Abstract

The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediates central to the cyclization. Methods reviewed include carbon-heteroatom ionization, double bond functionalization, nucleophilic addition, or electrocyclic ring opening. Additional variations, such as iso- and imino-Nazarov cyclization, employ unconventional substrates to produce new pentacycles. Here we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization.

Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward the Synthesis of Phomactin A

Co-reporter:Jennifer Ciesielski, Vincent Gandon, and Alison J. Frontier

The Journal of Organic Chemistry 2013 Volume 78(Issue 19) pp:9541-9552

Publication Date(Web):May 31, 2013

DOI:10.1021/jo4007514

A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic alkynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation–olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process.

Efficient Nazarov Cyclization/WagnerMeerwein Rearrangement Terminated by a CuII-Promoted Oxidation: Synthesis of 4-Alkylidene Cyclopentenones

Co-reporter:Dr. David Lebœuf;Eric Theiste; Vincent Gon;Stephanie L. Daifuku; Michael L. Neidig; Alison J. Frontier

Chemistry - A European Journal 2013 Volume 19( Issue 15) pp:4842-4848

Publication Date(Web):

DOI:10.1002/chem.201203396

Abstract

The discovery and elucidation of a new Nazarov cyclization/Wagner–Meerwein rearrangement/oxidation sequence is described that constitutes an efficient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways.

Reagent Control of [1,2]-WagnerMeerwein Shift Chemoselectivity Following the Nazarov Cyclization: Application to the Total Synthesis of Enokipodin B

Co-reporter:Dr. David Lebœuf;Christopher M. Wright ; Alison J. Frontier

Chemistry - A European Journal 2013 Volume 19( Issue 15) pp:4835-4841

Publication Date(Web):

DOI:10.1002/chem.201203395

Abstract

An approach toward the carbon framework of various sesquiterpenes from the herbertane and cuparane families is described, including the concise total synthesis of enokipodin B. The key step is the construction of the vicinal quarternary centers of the skeleton through a tandem Nazarov cyclization/Wagner–Meerwein rearrangement mediated by a copper(II) complex. During this study, it was also found that changing the ligand architecture on the copper(II) promoter improved the chemoselectivity of the cationic rearrangement.

Experimental and Theoretical Studies on the Nazarov Cyclization/Wagner–Meerwein Rearrangement Sequence

Co-reporter:David Lebœuf ; Vincent Gandon ; Jennifer Ciesielski

Journal of the American Chemical Society 2012 Volume 134(Issue 14) pp:6296-6308

Publication Date(Web):April 3, 2012

DOI:10.1021/ja211970p

Highly functionalized cyclopentenones can be generated by a chemoselective copper(II)-mediated Nazarov/Wagner–Meerwein rearrangement sequence of divinyl ketones. A detailed investigation of this sequence is described including a study of substrate scope and limitations. After the initial 4π electrocyclization, this reaction proceeds via two different sequential [1,2]-shifts, with selectivity that depends upon either migratory ability or the steric bulkiness of the substituents at C1 and C5. This methodology allows the creation of vicinal stereogenic centers, including adjacent quaternary centers. This sequence can also be achieved by using a catalytic amount of copper(II) in combination with NaBAr4f, a weak Lewis acid. During the study of the scope of the reaction, a partial or complete E/Z isomerization of the enone moiety was observed in some cases prior to the cyclization, which resulted in a mixture of diastereomeric products. Use of a Cu(II)-bisoxazoline complex prevented the isomerization, allowing high diastereoselectivity to be obtained in all substrate types. In addition, the reaction sequence was studied by DFT computations at the UB3LYP/6-31G(d,p) level, which are consistent with the proposed sequences observed, including E/Z isomerizations and chemoselective Wagner–Meerwein shifts.

Cyclization Cascades Initiated by 1,6-Conjugate Addition

Co-reporter:Joshua L. Brooks

Journal of the American Chemical Society 2012 Volume 134(Issue 40) pp:16551-16553

Publication Date(Web):September 24, 2012

DOI:10.1021/ja308451y

Dienyl diketones containing tethered acetates selectively undergo two different 1,6-conjugate addition-initiated cyclization cascades. One is a 1,6-conjugate addition/cyclization sequence with incorporation of the nucleophile, and the other is catalyzed by DABCO and is thought to proceed via a cyclic acetoxonium intermediate. The reaction behavior of substrates lacking the tethered acetate was also studied. The scope of both types of cyclization cascades, the role of the amine additive, and the factors controlling reactivity and selectivity in the two different reaction pathways is discussed.

A Macrocyclic β-Iodoallenolate Intermediate Is Key: Synthesis of the ABD Core of Phomactin A

Co-reporter:Jennifer Ciesielski, Kevin Cariou, and Alison J. Frontier

Organic Letters 2012 Volume 14(Issue 16) pp:4082-4085

Publication Date(Web):August 2, 2012

DOI:10.1021/ol3017116

An enantioselective strategy for the synthesis of phomactin natural products is described. The Lewis acid triggered cyclization of a β-iodoallenolate embedded in a 12-membered macrocycle was used to obtain a highly functionalized bicyclo[9.3.1]pentadecane in good yield and high diastereoselectivity. This iodoenone contains the substituents of the AD ring system of the phomactin family of natural products, appropriate for further functionalization. Synthesis of the oxadecalin core of phomactin A from the AD iodoenone intermediate was achieved. In this unusual strategy, rings A and B are both fashioned within a macrocyclic precursor.

Total Synthesis of (±)-Rocaglamide via Oxidation-Initiated Nazarov Cyclization

Co-reporter:John A. Malona, Kevin Cariou, William T. Spencer III, and Alison J. Frontier

The Journal of Organic Chemistry 2012 Volume 77(Issue 4) pp:1891-1908

Publication Date(Web):January 26, 2012

DOI:10.1021/jo202366c

This article describes the evolution of a Nazarov cyclization-based synthetic strategy targeting the anticancer, antiinflammatory, and insecticidal natural product (±)-rocaglamide. Initial pursuit of a polarized heteroaromatic Nazarov cyclization to construct the congested cyclopentane core revealed an unanticipated electronic bias in the pentadienyl cation. This reactivity was harnessed in a successful second-generation approach using an oxidation-initiated Nazarov cyclization of a heteroaryl alkoxyallene. Full details of these two approaches are given, as well as the characterization of undesired reaction pathways available to the Nazarov cyclization product. A sequence of experiments that led to an understanding of the unexpected reactivity of this key intermediate is described, which culminated in the successful total synthesis of (+)-rocaglamide.

Cycloaromatization Protocol for Synthesis of Polysubstituted Phenol Derivatives: Method Development and Mechanistic Studies

Co-reporter:William T. Spencer III and Alison J. Frontier

The Journal of Organic Chemistry 2012 Volume 77(Issue 17) pp:7730-7736

Publication Date(Web):August 14, 2012

DOI:10.1021/jo3010952

The scope of the cycloaromatization of propargylic ethers was explored using operationally simple air- and moisture-insensitive conditions. Highly substituted phenol derivatives were obtained in high yields. Mechanistic experiments indicate that the reaction occurs by an electrocyclization followed by 1,3-proton transfer.

Divergent Reaction Pathways of a Cationic Intermediate: Rearrangement and Cyclization of 2-Substituted Furyl and Benzofuryl Enones Catalyzed by Iridium(III)

Co-reporter:Tulaza Vaidya ; Gerald F. Manbeck ; Sylvia Chen ; Alison J. Frontier ;Richard Eisenberg

Journal of the American Chemical Society 2011 Volume 133(Issue 10) pp:3300-3303

Publication Date(Web):February 15, 2011

DOI:10.1021/ja111317q

In contrast to 2-substituted pyrrole enones, furyl and benzofuryl enones do not undergo the Nazarov electrocyclization. Instead, these furyl and benzofuryl enones exhibit unusual rearrangement sequences in the presence of catalytic amounts of [IrBr(CO)(DIM)((R)-(+)-BINAP)](SbF6)2 (1; DIM = diethylisopropylidene malonate) and AgSbF6 (1:1). A 1,2-H shift followed by intramolecular Friedel−Crafts alkylation leads to synthetically valuable cyclohexanones with furanylic quaternary centers. The electrophilicity of 1 is essential for this rearrangement.

Understanding the Fate of the Oxyallyl Cation following Nazarov Electrocyclization: Sequential Wagner−Meerwein Migrations and the Synthesis of Spirocyclic Cyclopentenones

Co-reporter:Jie Huang ; David Lebœuf

Journal of the American Chemical Society 2011 Volume 133(Issue 16) pp:6307-6317

Publication Date(Web):April 5, 2011

DOI:10.1021/ja111504w

A general reaction sequence is described that involves Nazarov cyclization followed by two sequential Wagner−Meerwein migrations, to afford spirocyclic compounds from divinyl ketones in the presence of 1 equiv of copper(II) complexes. A detailed investigation of this sequence is described including a study of substrate scope and limitations. It was found that after 4π electrocyclization, two different pathways are available to the oxyallyl cation intermediate: elimination of a proton can give the usual Nazarov cycloadduct, or ring contraction can give an alternative tertiary carbocation. After ring contraction, either [1,2]-hydride or carbon migration can occur, depending upon the substitution pattern of the substrate, to furnish spirocyclic products. The rearrangement pathway is favored over the elimination pathway when catalyst loading is high and the copper(II) counterion is noncoordinating. Several ligands were found to be effective for the reaction. Thus, the reaction sequence can be controlled by judicious choice of reaction conditions to allow selective generation of richly functionalized spirocycles. The three steps of the sequence are stereospecific: electrocyclization followed by two [1,2]-suprafacial Wagner−Meerwein shifts, the ring contraction and then a hydride, alkenyl, or aryl shift. The method allows stereospecific installation of adjacent stereocenters or adjacent quaternary centers arrayed around a cyclopentenone ring.

Conjugate Addition-Initiated Nazarov Cyclization

Co-reporter:Joshua L. Brooks ; Patrick A. Caruana

Journal of the American Chemical Society 2011 Volume 133(Issue 32) pp:12454-12457

Publication Date(Web):July 22, 2011

DOI:10.1021/ja205440x

A reaction sequence involving the 1,6-conjugate addition of a nucleophile to a dienyl diketone followed by Nazarov cyclization is described. Several nucleophiles are identified as competent initiators for the sequence. A different reaction outcome is observed when catalytic amounts of nucleophile are employed, involving elimination of the nucleophile after the electrocyclization.

Catalytic Nazarov Cyclization: The State of the Art

Co-reporter:Tulaza Vaidya; Richard Eisenberg; Alison J. Frontier

ChemCatChem 2011 Volume 3( Issue 10) pp:1531-1548

Publication Date(Web):

DOI:10.1002/cctc.201100137

Using Nazarov Electrocyclization to Stage Chemoselective [1,2]-Migrations: Stereoselective Synthesis of Functionalized Cyclopentenones

Co-reporter:Dr. David Lebœuf;Dr. Jie Huang; Vincent Gon; Alison J. Frontier

Angewandte Chemie International Edition 2011 Volume 50( Issue 46) pp:10981-10985

Publication Date(Web):

DOI:10.1002/anie.201104870

Using Nazarov Electrocyclization to Stage Chemoselective [1,2]-Migrations: Stereoselective Synthesis of Functionalized Cyclopentenones

Co-reporter:Dr. David Lebœuf;Dr. Jie Huang; Vincent Gon; Alison J. Frontier

Angewandte Chemie 2011 Volume 123( Issue 46) pp:11173-11177

Publication Date(Web):

DOI:10.1002/ange.201104870

A Highly Reactive Dicationic Iridium(III) Catalyst for the Polarized Nazarov Cyclization Reaction

Co-reporter:Tulaza Vaidya;AbdurrahmanC. Atesin Dr.;IldikoR. Herrick Dr.;AlisonJ. Frontier ;Richard Eisenberg

Angewandte Chemie 2010 Volume 122( Issue 19) pp:3435-3438

Publication Date(Web):

DOI:10.1002/ange.201000100

A Highly Reactive Dicationic Iridium(III) Catalyst for the Polarized Nazarov Cyclization Reaction

Co-reporter:Tulaza Vaidya;AbdurrahmanC. Atesin Dr.;IldikoR. Herrick Dr.;AlisonJ. Frontier ;Richard Eisenberg

Angewandte Chemie International Edition 2010 Volume 49( Issue 19) pp:3363-3366

Publication Date(Web):

DOI:10.1002/anie.201000100

Dicationic Palladium(II) Complexes as Active Lewis Acid Catalysts for Polarized Nazarov Cyclization

Co-reporter:Jing Zhang, Tulaza Vaidya, William W. Brennessel, Alison J. Frontier and Richard Eisenberg

Organometallics 2010 Volume 29(Issue 15) pp:3341-3349

Publication Date(Web):July 12, 2010

DOI:10.1021/om100274g

Two new bidentate phosphonamidite ligands − 1,2-bis((3αS)-3,3-diphenyltetrahydro-2-oxa-6α-aza-1-phosphapentaleno)ethane, L1, and 1,2-bis((3αS)-3,3-diphenyltetrahydro-2-oxa-6α-aza-1-phosphapentaleno)benzene, L2 − were prepared from (S)-α,α-diphenylprolinol and either 1,2-bis(dichlorophosphino)ethane or 1,2-bis(dichlorophosphino)benzene, respectively. Reactions of L1 and L2 with one equivalent of Pd(PhCN)2Cl2 in dichloromethane result in the formation of the neutral complexes Pd(L1-P,P)Cl2, 2, and Pd(L2-P,P)Cl2, 3, in good yields (85% and 92%, respectively). Complexes 2 and 3 were fully characterized by NMR spectroscopy, elemental analyses, and X-ray crystallography. Chloride abstraction from 1 and 2 using two equivalents of AgSbF6 in the presence of excess diethylisopropylidene malonate (DIM) leads to the formation of the respective dicationic palladium complexes [Pd(L1-P,P)(DIM)][SbF6]2, 4, and [Pd(L2-P,P)(DIM)][SbF6]2, 5. As a result of the cationic nature of 4 and 5 and the labile coordination of DIM, these complexes exhibit high activity as electrophilic catalysts for the Nazarov cyclization of electronically polarized substrates. For those substrates in which a quaternary carbon center is generated upon Nazarov cyclization, spirocycle formation occurs via a Wagner−Meerwein rearrangement following cyclization. In these cases, addition of NaBAr4f as a cofactor to the reaction system improves the selectivity to spirocycle formation relative to the simple Nazarov product.

Nazarov Cyclization Initiated by Peracid Oxidation: The Total Synthesis of (±)-Rocaglamide

Co-reporter:John A. Malona ; Kevin Cariou

Journal of the American Chemical Society 2009 Volume 131(Issue 22) pp:7560-7561

Publication Date(Web):May 15, 2009

DOI:10.1021/ja9029736

The total syntheses of aglafolin, rocagloic acid, and rocaglamide using Nazarov cyclization are described. Generation of the necessary oxyallyl cation intermediate was accomplished via peracid oxidation of an allenol ether to generate an unusual oxycarbenium ion species that undergoes cyclization. The synthesis is efficient, highly diastereoselective, and strategically distinct from previous syntheses of rocaglamide.

β-Iodoallenolates as Springboards for Annulation Reactions

Co-reporter:Jennifer Ciesielski, Daniel P. Canterbury and Alison J. Frontier

Organic Letters 2009 Volume 11(Issue 19) pp:4374-4377

Publication Date(Web):September 8, 2009

DOI:10.1021/ol901721y

β-Iodoallenolates II, generated from alkynones I with tetra-n-butylammonium iodide and a Lewis acid, underwent selective single or double annulation, depending on the Lewis acid promoter. Treatment with TiCl4 gave cyclohexenyl alcohols III, whereas BF3·OEt2 gave oxadecalins IV. The scope and limitations of the two annulation reactions are described.

A torquoselective extrusion of isoxazoline N-oxides. Application to the synthesis of aryl vinyl and divinyl ketones for Nazarov cyclization

Co-reporter:Daniel P. Canterbury, Ildiko R. Herrick, Joann Um, K.N. Houk, Alison J. Frontier

Tetrahedron 2009 65(16) pp: 3165-3179

Publication Date(Web):

DOI:10.1016/j.tet.2008.10.003