Thesis advisor: Amir H. Hoveyda / Catalytic enantioselective reactions are of great importance in synthetic organic chemistry. Thus, development of efficient, selective and easily accessible catalyst for various bond formations is the main task in our laboratories. First, we have developed the first broadly applicable enantioselective boryl conjugate addition reactions to a variety of α,β-unsaturated carbonyls, promoted by a chiral Lewis basic N-heterocyclic carbene. The valuable β-boryl carbonyls were further used in complex molecule syntheses. The mechanism of these C–B bond formations was studied in details. We have also developed a practical method for enantioselective addition of an allene unit to aryl-, heteroaryl- and alkyl-substituted Boc-aldimines. These efficient C–C bond formations, catalyzed by an aminophenol-derived boron-based catalyst, were further utilized in succinct syntheses of anisomycin and epi-cytoxazone. Finally, chiral NHC–Cu complexes were employed for site-, diastereo- and enantioselective silyl conjugate additions to acyclic and cyclic dienones and dienoates. The precious enantiomerically enriched allylsilane obtained can be converted into a ketone-aldol type product, which is difficult to access through alternative methods. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The Morita-Baylis-Hillman (MBH) reaction is a very versatile synthetic protocol to synthesize various useful compounds containing several functional groups. MBH acetates and carbonates are highly valued compounds as they have good potential to be precursors for organic synthesis reactions due to their ease of modification and synthesis. This thesis utilizes Density Functional Theory (DFT) calculations to understand the mechanism and selectivity of an unexpected tandem conjugate addition-elimination (CA-E) reaction of allylic alkylated Morita-Baylis-Hillman C- adducts. This synthetic protocol was developed by Prof. Zhi-Yong Jiang and co-workers from Henan University, China. The reaction required the use of sub-stoichiometric amounts of an organic or inorganic Brøndst base as a catalyst and was achieved with excellent yields (96%) in neat conditions. TBD gave the highest yield amongst the organocatalysts and Cs2CO3 gave the highest yield amongst all screened bases. A possible mechanistic pathway was proposed and three different energy profiles were modeled using 1,5,7-triaza-bicyclo-[4.4.0]-dec-5-ene (TBD), Cs2CO3 and CO32- as catalysts. All three models were able to explain the experimental observations, revealing both kinetic and thermodynamic factors influencing the selectivity of the CA-E reaction. CO32- model gave the most promising result, revealing a significant energy difference of 17.9 kcal/mol between the transition states of the two differing pathways and an energy difference of 20.9 kcal/mol between the two possible products. Although TBD modeling did not show significant difference in the transition states of the differing pathways, it revealed an unexpected secondary non-covalent electrostatic interaction, involving the electron deficient C atom of the triaza CN3 moiety of the TBD catalyst and the O atom of a neighboring NO2- group in the intermediate. Subsequent modeling using a similar substrate proved the possibility of this non-covalent electrostatic interaction, as there was significant overlap of the orbital cloud present in both the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) of the molecule between the C atom of the triaza moiety belonging to the TBD catalyst and the O atom of the nitro group of the substrate. The Mayer bond order was of the C-O interaction was determined to be 0.138.

This report details the discovery of a method for rhodium catalyzed asymmetric conjugate additions of heteroaryl nucleophiles to α,β-unsaturated carbonyl compounds. This work has successfully employed heteraryl titanates in enantioselective conjugate addition to α,β-unsaturated carbonyl compounds for the first time. Moreover, the utility of benzofuranyl, benzothiophenyl, and pyrrolo zinc reagents has been exemplified in enantioselective conjugate additions. We have found that the precatalyst [Rh(COD)acac]/OMeBIPHEP is broadly effective for enantioselective conjugate additions. Each heterocycle tested exhibited unique reactivity with respect to both conversion and enantioselectivity; reactivities of heteroaryl zinc reagents and heteroaryl titanates in enantioselective conjugate additions to α,β-unsaturated carbonyl compounds are sometimes complementary. Efforts directed towards the development of a method for rhodium-free enantioselective conjugate addition of furan to α,β-unsaturated carbonyl compounds are also described. / text

Thesis advisor: Amir H. Hoveyda / Chapter 1. The development of chiral monodentate N-heterocyclic carbenes (NHCs) is presented. Structurally varied twenty-eight new chiral imidazolinim salts, NHC precursors, were synthesized and characterized. Chapter 2. The first example of Cu-catalyzed enantioselective conjugate additions of alkyl- and arylzinc reagents to unactivated cyclic enones is presented. Transformations are promoted in the presence of 2.5-15 mol % of a readily available chiral NHC-based Cu complex, affording the desired products bearing all-carbon quaternary stereogenic centers in 67-98% yield and in up to 97% ee. Catalytic enantioselective reactions can be carried out on a benchtop, with undistilled solvent and commercially available (not further purified) Cu salts. Chapter 3. A new class of enantioselective conjugate addition (ECA) reactions that involve aryl- or alkenylsilylfluoride reagents and are catalyzed by chiral non-C2-symmetric Cu-based NHC complexes are presented. Transformations have been designed based on the principle that a catalytically active chiral NHC-Cu-aryl or NHC-Cu-alkenyl complex can be accessed from reaction of a Cu-halide precursor with in situ-generated aryl- or alkenyl-tetrafluorosilicate. Reactions proceed in the presence of 1.5 equivalents of the aryl- or alkenylsilane reagents and 1.5 equivalents of tris(dimethylamino)sulfonium difluorotrimethylsilicate. Desired products are isolated in 63-97% yield and 73.5:26.5-98.5:1.5 enantiomeric ratio (47%-97% ee). Chapter 4. An efficient Cu-catalyzed protocol for enantioselective addition of a dimethylphenylsilanyl group to a wide range of cyclic and acyclic unsaturated ketones, esters, acrylonitriles and dienones is presented. Reactions are performed in the presence of 1-5 mol % of commercially available and inexpensive CuCl, a readily accessible monodentate imidazolinium salt as well as commercially available (dimethylphenylsilyl)pinacolatoboron. Cu-catalyzed 1,4- and 1,6-conjugate additions afford the enantiomerically enriched silanes in 72%-98% yield and 90:10->99:1 enantiomeric ratio (er) with up to >25:1 of Z:E selectivity. Chapter 5. A Cu-catalyzed method for enantioselective boronate conjugate additions to trisubstituted alkenes of acyclic a,b-unsaturated carboxylic esters, ketones, and thioesters is presented. All transformations are promoted by 5 mol % of a chiral monodentate NHC-Cu complex, derived from a readily available C1-symmetric imidazolinium salt, and in the presence of commercially available bis(pinacolato)diboron. Reactions are efficient (typically, 60% to >98% yield after purification) and deliver the desired boryl carbonyls in up to >98:2 enantiomer ratio (er). In addition, metal-free, nucleophilic activation of a B-B bond has been exploited in the development of a highly efficient method for conjugate additions of commercially available bis(pinacolato)diboron to cyclic or acyclic a,b-unsaturated carbonyls. Reactions are readily catalyzed by 2.5-10 mol % of a simple NHC. A variety of cyclic and acyclic unsaturated ketones and esters can serve as substrates. Transformations deliver boryl carbonyls bearing tertiary as well as quaternary B-substituted carbons in up to >98% yield. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Marc L. Snapper / Chapter 1. A Practical Synthesis of 3-Acyl Cyclobutanones by [2 + 2] Annulation. Mechanism and Utility of the Zn(II)-Catalyzed Condensation of alpha-Chloroenamines with Electron-Deficient Alkenes. We have developed a catalytic method for the synthesis of highly functionalized 3-acyl cyclobutanones which are useful building blocks for a variety of natural products. Methods for cyclobutanone synthesis have traditionally been limited to Lewis-acid promoted rearrangement of oxaspiropentanes or cyclizations of ketene and syntheses involving keteneiminium salts have required stoichiometric quantities of a Lewis acid. Furthermore, the mechanism for these types of cyclizations remains unknown. This portion of my research focused on an efficient, catalytic method for the synthesis of 3- acyl cyclobutanones and providing insight into the mechanism for cycloaddition. Chapter 2. Enantioselective Synthesis of Boron-Substituted Quaternary Carbons by NHC-Cu-Catalyzed Boronate Conjugate Additions to Unsaturated Carboxylic Esters, Ketones, or Thioesters. We have developed an enantioselective NHC-Cu-catalyzed conjugate addition of boronate esters to acyclic, trisubstituted alpha, beta-unsaturated carbonyl compounds. Enantioselective conjugate addition of a boronic acid pinacol ester through the use of bis(pinacolato)diboron [B2(pin)2,] to alpha, beta-unsaturated aliphatic and aryl esters promoted by 5 mol % of an NHC-Cu catalyst afforded tertiary beta-boryl carbonyls in high efficiency and enantioselectivity. Trisubstituted alpha, beta-unsaturated esters and thioesters were found to be reactive substrates in the presence of a stoichiometric quantity of methanol. Chapter 3. Metal-Free Catalytic C-Si Bond Formation in an Aqueous Medium and C-B Bond Formation in a Protic Medium. Enantioselective NHC-Catalyzed Silyl and Boryl Conjugate Additions to Cyclic and Acyclic alpha, beta-Unsaturated carbonyls. We have developed a method for enantioselective metal-free silyl conjugate additions through the use of dimethylphenylsilyl) boronic acid pinacol ester [PhMe2SiB(pin)] catalyzed by chiral N-heterocyclic carbenes (NHCs) in basic aqueous thf. Optimization of metal-free conditions demonstrated that the presence of water was required for high efficiency. alpha, beta-Unsaturated cyclic ketones and lactones were examined as substrates, and acyclic ketones, esters and aldehydes were also competent substrates for silyl conjugate addition. beta-Silyl carbonyls were isolated in up to >98% yield and >98:2 er. Chapter 4. Elucidation of Mechanism for Enantioselective NHC-Catalyzed Silyl Conjugate Addition. We propose a catalytic cycle for NHC-catalyzed enantioselective silyl conjugate addition. Mechanistic studies of NHC-catalyzed enantioselective silyl conjugate additions are presented. Optimization of conditions for an inefficient alpha, beta-unsaturated electron-deficient ketone provided insight into the roles for dbu and water. Kinetic data indicate that conjugate addition is first order in PhMe2SiB(pin) and carbene, and DFT calculations support the formation of an NHC-silyl anion as a reactive intermediate in the catalytic cycle. / Thesis (PhD) — Boston College, 2012. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1 Catalytic Enantioselective Addition of Organoaluminum Reagents Catalytic methods involving the enantioselective addition of both commercially available as well as in situ generated organoaluminum reagents are reviewed. An overview of additions to aldehydes, ketones, and imines is provided as well as the difficulties and limitations of such transformations. Furthermore, additions to unsaturation adjacent to a leaving group to form a new stereogenic center are examined. Finally, conjugate addition reactions wherein an organoaluminum reagent is added to an olefin adjacent to a carbonyl or nitro group are discussed. Chapter 2 Synthesis of Quaternary Carbon Stereogenic Centers through Enantioselective Cu-Catalyzed Allylic Substitution with Alkenylaluminum Reagents A method for the formation of 1,4-diene containing quaternary stereogenic centers through catalytic enantioselective allylic substitution is disclosed. The addition of alkyl- and aryl-substituted alkenylaluminum reagents to trisubstituted allylic phosphates is promoted by 0.5–2.5 mol % of a sulfonate-containing bidentate N-heterocyclic carbene–copper complex. Products containing a quaternary stereogenic center as well as a newly formed terminal olefin are obtained in up to 97% yield and 99:1 er with high site selectivity (>98:2 SN2’:SN2). The requisite nucleophiles are generated in situ through hydroalumination of terminal alkynes. The utility of the method is demonstrated through a concise synthesis of natural product bakuchiol. Chapter 3 A Multicomponent Ni-, Zr-, Cu-Catalyzed Strategy for Enantioselective Synthesis of Alkenyl-Substituted Quaternary Carbons Despite the widespread use of conjugate addition in organic synthesis, few reports pertain to the addition of nucleophiles to acyclic systems and none in which the nucleophile is an alkene. Herein, we report the first examples of enantioselective conjugate addition of alkenylmetal reagents to trisubstituted enones to form all-carbon quaternary stereogenic centers. Alkenylaluminum nucleophiles are prepared through a site-selective Ni-catalyzed hydroalumination of terminal alkynes and the requisite E-trisubsituted enones are the products of a regioselective Zr-catalyzed carboalumination/acylation of a terminal alkyne. Products are obtained in up to 97% yield and 99:1 er. A model for enantioselectivity, supported by DFT calculations, is proposed. Chapter 4 Formation of Tertiary Centers through Catalytic Enantioselective Conjugate Addition of Alkenylaluminum Reagents to Acyclic Enones We have developed an enantioselective NHC–Cu catalyzed synthesis of tertiary centers in acyclic systems using in situ generated alkenylaluminum reagents, as current methods typically rely on Rh-catalysis at high temperatures with alkenyl boronic acids in protic solvents. Moreover, most examples include chalcone-derived substrates, which, while more reactive, often preclude further functionalization. With the current method, we are able to couple a variety of alkenyl nucleophiles with α,β-unsaturated ketones. E- or Z-silylalkenylaluminum reagents, derived from hydroalumination of silyl-protected alkynes, lead to products in good yields and high enantioselectivities. Additionally, both the α- and β-alkenylaluminum reagents participate in the reaction. Chapter 5 Development of N-Heterocyclic Carbene–Cu Catalyzed Allylic Substitution of Diboryl Methane to Morita-Baylis-Hillman Derived Allylic Phosphates We have developed a method for the coupling of a geminyl diboron reagent with Morita-Baylis-Hillman derived trisubstituted ester-containing allylic phosphates. With 10 mol % of an in situ generated NHC–Cu complex and 1.5 equivalents of the boron reagent, we are able to form the desired product in high regio- and enantioselectivity with a 2,5-ditert-butyl containing carbene. Simple aryl substituents as well as those containing a halogen or an electron-withdrawing group furnish the desired products in up to 85% yield and 98:2 er. Alkyl-containing substrates are also competent reaction partners, although longer chain aliphatics results in slightly diminished enantioselectivity. We are pursuing the application of this method to the synthesis of α-methylene lactones which can be further functionalized to natural products like tubulin polymerization inhibitor (–)-steganone and glaucoma medication (+)-pilocarpine. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

A set of studies centered around the reactions of the active methine compound 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene (the "ring-opened adduct"), obtained by base-induced ring-opening of the Diels-Alder adduct of 5,5-dicyanocyclopentadiene and methyl acrylate, has been carried out. A plan was devised for the anionic (at the dicyanomethyl carbon) ring-opened adduct whereby its reaction with electrophiles, for example Michael reactions with double-bond acceptors, would generate reactive intermediates that would undergo cyclization by tandem conjugate addition to the a,ß,?,d-unsaturated ring p-system to generate bicyclic compounds. In practice, reaction with di-<i>tert</i>-butyl methylidenemalonate, methyl vinyl ketone, and cyclopentenone generated intermediates that exhibited greater tandem reactivity than was anticipated: the bicyclic enolates were found to cyclize further by Thorpe-Ziegler-like reaction with the proximal nitrile to generate, after facile acid hydrolysis, substituted known tricyclic skeleta termed homobrendanes, specifically, tricyclo[5. 2. 1. 0^4,8]decenes. An attempt was made to generalize the reaction to other substrates, among them singly-activated Michael acceptors and 1,2-heteroatom electrophiles, but the generalization of the homobrendane forming reaction did not meet with success. Attempted functional group manipulations to probe the conversion of the homobrendane derived from di-<i>tert</i>-butyl methylidenemalonate to the homobrendane natural product 2-isocyanoallopupukeanane revealed the unreactivity of the skeletal double-bond toward electrophiles and the high reactivity of the ring ketone toward nucleophiles, among them mCPBA which brought about Baeyer-Villiger reaction, and chloride and hydroxide, which brought about addition/elimination reactions to cleave the last-formed homobrendane ring. <br /> The ring-opened adduct was also envisaged as a potential substrate in intramolecular Heck reactions. To this end, Heck substrates were generated from the ring-opened adduct anion and iodo- and bromo-benzyl halides. A key observation at this stage pertained to the unexpected acidity of the ring-opened adduct C5 proton, which could be deprotonated by DBU to bring about allylic isomerization, a finding that would provide a key insight to the pattern of reactivity later evidenced with alkyl propiolates. Optimization of the Heck substrate-generating reaction was followed by Heck reactions under Jeffery's conditions, which generated angular tricycles as intended, accompanied by aromatic compounds generated by base-induced HCN elimination/rearrangement and dehydrogenation. The Jeffery's conditions were optimized to limit the production of aromatics. <br /> The possibility of ring-opened adduct-derived vinyl silane intermediates undergoing cationic cyclizations led to a minor study based upon the bromination of allylsilanes and the elimination of TMSBr from 1,2-dibromo-3-trimethylsilyl compounds, accessible compounds unaccounted for in the review literature. It was determined that the combination of HBr and Br₂ (perhaps as HBr₃) was required to eliminate TMSBr, in contravention of the textbook account of electrophilic substitutions being the inherent reactions of allylsilanes and Br₂. <br /> Unexpected tandem reactivity was observed in the reactions of the anionic ring-opened adduct and alkyl propiolates under catalytic DBU conditions. Rather than tandem cyclization or simple adduct formation, the allenolate intermediates were determined to undergo extremely facile formal allenolate Cope rearrangements involving the ?,d-double-bond of the parent ring. Excess base intercepted the allenolate by deprotonating ring C5 and effecting 1,2-vinyl transfer by 3-<i>exo</i>-trig addition-elimination. The chemistry of the highly delocalized side-chain carbanion in the Cope product was studied in detail.

A set of studies centered around the reactions of the active methine compound 1-carbomethoxy-5-dicyanomethyl-1,3-cyclohexadiene (the "ring-opened adduct"), obtained by base-induced ring-opening of the Diels-Alder adduct of 5,5-dicyanocyclopentadiene and methyl acrylate, has been carried out. A plan was devised for the anionic (at the dicyanomethyl carbon) ring-opened adduct whereby its reaction with electrophiles, for example Michael reactions with double-bond acceptors, would generate reactive intermediates that would undergo cyclization by tandem conjugate addition to the a,ß,?,d-unsaturated ring p-system to generate bicyclic compounds. In practice, reaction with di-<i>tert</i>-butyl methylidenemalonate, methyl vinyl ketone, and cyclopentenone generated intermediates that exhibited greater tandem reactivity than was anticipated: the bicyclic enolates were found to cyclize further by Thorpe-Ziegler-like reaction with the proximal nitrile to generate, after facile acid hydrolysis, substituted known tricyclic skeleta termed homobrendanes, specifically, tricyclo[5. 2. 1. 0^4,8]decenes. An attempt was made to generalize the reaction to other substrates, among them singly-activated Michael acceptors and 1,2-heteroatom electrophiles, but the generalization of the homobrendane forming reaction did not meet with success. Attempted functional group manipulations to probe the conversion of the homobrendane derived from di-<i>tert</i>-butyl methylidenemalonate to the homobrendane natural product 2-isocyanoallopupukeanane revealed the unreactivity of the skeletal double-bond toward electrophiles and the high reactivity of the ring ketone toward nucleophiles, among them mCPBA which brought about Baeyer-Villiger reaction, and chloride and hydroxide, which brought about addition/elimination reactions to cleave the last-formed homobrendane ring. <br /> The ring-opened adduct was also envisaged as a potential substrate in intramolecular Heck reactions. To this end, Heck substrates were generated from the ring-opened adduct anion and iodo- and bromo-benzyl halides. A key observation at this stage pertained to the unexpected acidity of the ring-opened adduct C5 proton, which could be deprotonated by DBU to bring about allylic isomerization, a finding that would provide a key insight to the pattern of reactivity later evidenced with alkyl propiolates. Optimization of the Heck substrate-generating reaction was followed by Heck reactions under Jeffery's conditions, which generated angular tricycles as intended, accompanied by aromatic compounds generated by base-induced HCN elimination/rearrangement and dehydrogenation. The Jeffery's conditions were optimized to limit the production of aromatics. <br /> The possibility of ring-opened adduct-derived vinyl silane intermediates undergoing cationic cyclizations led to a minor study based upon the bromination of allylsilanes and the elimination of TMSBr from 1,2-dibromo-3-trimethylsilyl compounds, accessible compounds unaccounted for in the review literature. It was determined that the combination of HBr and Br₂ (perhaps as HBr₃) was required to eliminate TMSBr, in contravention of the textbook account of electrophilic substitutions being the inherent reactions of allylsilanes and Br₂. <br /> Unexpected tandem reactivity was observed in the reactions of the anionic ring-opened adduct and alkyl propiolates under catalytic DBU conditions. Rather than tandem cyclization or simple adduct formation, the allenolate intermediates were determined to undergo extremely facile formal allenolate Cope rearrangements involving the ?,d-double-bond of the parent ring. Excess base intercepted the allenolate by deprotonating ring C5 and effecting 1,2-vinyl transfer by 3-<i>exo</i>-trig addition-elimination. The chemistry of the highly delocalized side-chain carbanion in the Cope product was studied in detail.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第18814号 / 理博第4072号 / 新制||理||1586(附属図書館) / 31765 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 大須賀 篤弘, 教授 時任 宣博 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20947号 / 理博第4399号 / 新制||理||1632(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 依光 英樹, 教授 大須賀 篤弘 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM