Over the past two decades and continuing on, carbonyl allylation chemistry has been a very useful and popular tool for the stereocontrolled formation of carbon-carbon bonds in the field of organic synthesis. In the context of natural product synthesis, the efficiency and status of aldehyde allylboration method is only matched by the asymmetric and diastereoselective aldol methodology. Unfortunately, prior to the new millennium, the means to control the absolute stereoselectivity in the addition of allylic boron reagents had been restricted to stoichiometric chiral directors, appended onto the metal center. In 2002, the research groups of Hall and Miyaura reported a new Lewis acid-catalyzed allylboration reaction manifold, which raised intriguing mechanistic questions and also paved the way for a catalytic enantioselective methodology development. Chapter 2 of this thesis details mechanistic studies related to the new Lewis acid-catalyzed allylboration. In this chapter, various control experiments and kinetic studies are presented, the results of which allowed us to propose a hypothesis involving the electrophilic boronate activation as the key factor for the observed rate enhancement. Chapter 3 describes the initial phase of our research to develop a catalytic enantioselective allylboration methodology. We discovered that Brnsted acid catalysts derived from diolSnCl4 complexes were promising catalysts for the asymmetric addition of air and moisture stable and commercially available allylic pinacol boronates. Under this 1st generation catalyst-system, the corresponding homoallylic alcohols were obtained in moderate to good enantioselectivity and excellent diastereoselectivity. The development of a novel chiral Brnsted acid catalyst for the highly enantio- and diastereoselective allylboration reaction methodology is the single most important result to come from this thesis. Chapter 4 outlines the development of the 2nd generation catalyst system. A systematic study of the diol component of the catalyst system led us to arrive at a novel diol nicknamed Vivol on behalf of my contribution. The resulting Brnsted acid derived from VivolSnCl4 now provided the corresponding homoallylic alcohol products in very good to excellent enantioselectivity. Preliminary mechanistic studies along with the X-ray diffraction structure of the catalyst system are also presented. Based on this information, an even better performaning diol (termed F-Vivol) was developed. This 3rd generation catalyst system derived from F-VivolSnCl4 complex was shown to display consistently superior reactivity and selectivity over its 2nd generation predecessor. Chapter 5 describes our efforts to expand the reagent scope of the Brnsted acid catalyzed allylboration methodology. Furthermore, this chapter also describes the successful application of the catalytic process towards the synthesis of simple and complex molecules. Accordingly, the preparation and application of the Brnsted acid-catalyzed addition of 2-bromoallyl boron pinacolate is described. The successful transformation of the corresponding bromo-homoallylic alcohols to a compelling class of -butyrolactones is also presented. The later part of the Chapter presents the synthesis of natural products (+) dodoneine and palmerolide A.

No description available.

Thesis advisor: James P. Morken / Platinum-catalyzed enantioselective 1,4-diboration of cyclic 1,3-dienes is reported, providing enantioenriched 1,4-bis(boronic) esters in good yield and up to 96:4 er. The analogous diboration reaction of imines generated enantioenriched alpha-amino boronic esters, which are valuable therapeutic candidates and useful synthetic building blocks. Alpha-substituted allyl bis(boronic) esters, which are derived from 1,2-diboration of 1,3-dienes, undergo double allylation with 1,4-dicarbonyls to afford cyclic 1,4-diols bearing four contiguous stereocenters in a one-pot fashion with moderate to excellent diastereoselectivity. The development of a synthesis of geminal bis(boronic) esters is disclosed. These unique compounds were utilized in an alkoxide-promoted deborylative alkylation to access primary, secondary and tertiary boronic esters. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Allylboration reactions have been thoroughly utilized in organic chemistry since it was discovered that they could add in a nucleophilic fashion to aldehydes and ketones in 1964. Modification of allylboronates and the substrates that they can react with has been the focus of many research groups over the past three decades. Recent works have made use of catalysis to promote the addition of allylboronates that are generally otherwise unreactive toward various electrophiles. Chapter 2 will discuss the discovery that Brnsted acids can catalyze the addition of unreactive 2-alkoxycarbonyl allylboronates to aldehydes and that the diastereoselectivity of the reaction is determined by the electronic nature of the aldehyde. Ketones and imines are much less reactive than aldehydes towards allylboronates due to steric and electronic factors. As a result, new conditions are often required to promote the allylboration reaction of ketones and imines. Chapter 3 will briefly discuss the challenges that ketones present as substrates for allylboration reactions and show my attempts at achieving this transformation. Chapter 4 will describe imines and their associated challenges as substrates for allylboration reactions. However, once harnessed, these substrates provide easy access to -methylene -lactones when a 2-alkoxycarbonyl allylboronate is used as the allylating reagent. The modification of important or interesting molecules by making major or minor changes to a common core structure is the basis of diversity-oriented synthesis of combinatorial libraries. -Alkylidene -lactones and -alkylidene -lactams are biologically interesting compounds present in numerous natural products. Chapter 5 will discuss how the title compounds were modified by various metal-catalyzed coupling reactions to provide a diversity-oriented combinatorial library of -lactones and -lactams. Since -lactones are prevalent in many natural products, the application of 2-alkoxycarbonyl allylboronates to a target-oriented synthesis was intriguing. Unlike diversity-oriented synthesis, target oriented synthesis aims at synthesizing a single compound through any number of controlled steps, arriving at one specific product that is obtained as a pure isomer. Access to highly complex -lactones is often tedious, however, Chapter 6 will discuss how a simple, one-step allylboration reaction of a complex aldehyde with a 2-alkoxycarbonyl allylboronate can lead to a highly substituted -lactone. This -lactone can be further modified and transformed into chinensiolide B, a biologically active natural product isolated from a plant found in various locations in China.

No description available.

Thesis advisor: James P. Morken / This dissertation describes the first enantioselective 1,2-diboration of cis-substituted 1,3-dienes. In the presence of a platinum catalyst and TADDOL-derived phosphonite ligands, both 4,4-disubstituted and mono-cis-substituted 1,3-dienes undergo regioselective 1,2-diboration to afford the corresponding 1,2-diols upon oxidation in up to 98:2 er and high yield. By achieving enantioselective 1,2-diboration of 1,3-dienes, a new synthetic route to α-chiral (Z)-allylboronate reagents has been developed. In the presence of an aldehyde, these allyl bis(boronate) esters undergo highly diastereoselective allylboration reaction to afford enantioenriched 1,5-homoallylic alcohols bearing all-carbon quaternary centers or syn-propionate motifs. In the presence of 1,4-dicarbonyl compounds, the (Z)-allylboronates undergo a double allylation reaction to afford cyclohexanols with four contiguous stereocenters in good yield and moderate to excellent diastereoselectivity. The tandem diboration/double allylation has been applied to the total synthesis of pumilaside B aglyon, and the partial synthesis 1β-hydroxy arbusculin A and bromophycolide F. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Au cours de ces trente dernières années, les allylboranes, une classe particulière de composés organoborés, ont pris une place particulièrement importante en synthèse organique, principalement dans la synthèse stéréocontrôlée d'alcools homoallyliques par addition sur un aldéhyde. C'est dans ce contexte que s'inscrit mon travail de thèse qui a pour objectif la mise au point de voies d'accès originales à deux familles d'allylboronates alpha-hétérosubstitués et à l'étude de leur réactivité. Pour cela, nous nous sommes intéressés dans un premier temps au comportement de gamma-borylallylsilanes vis à vis de diverses espèces électrophiles, ce qui a permis d'accéder notamment à des alpha-fluoroallylboronates, précurseurs de (Z)-1-fluoro-1-alcènes et à des fluorures allyliques. D'autres électrophiles, hétéroatomiques ou carbonés, peuvent être utilisés pour conduire après refonctionnalisation par addition sur des aldéhydes à des alcools insaturés de structures variées. Dans une seconde partie, nous avons synthétisé des alpha-isocyanatoallylboronates par réarrangement sigmatropique [3,3] d'allylcyanates borylés. Ces intermédiaires réactionnels, particulièrement intéressants pour accéder en série optiquement active à des ènecarbamates cycliques à sept chaînons, sont également précurseurs de pyrrolidines tétrasubstituées selon un réarrangement jusqu'alors non décrit dans la littérature. / Over the last thirty years, allylboranes, a particular class of organoboron compounds, have found many valuable applications in organic synthesis, mainly in the stereoselective synthesis of homoallylic alcohols via addition to aldehydes. In this context, we have developed two novel families of alpha-heterosubstituted allylboronates. We first studied the behavior of gamma-borylallylsilanes towards various electrophilic species in order to access to alpha-fluoroallylboronates which are versatile precursors of various fluorinated molecules. Other heteroatom or carbon electrophiles could also be used to afford after refunctionalization with aldehydes structurally diverse unsaturated alcohols. In the second part of this thesis, we studied the reactivity of alpha-isocyanatoallylboronates prepared by [3,3] sigmatropic rearrangement of borylated allylcyanates. These intermediates have proven to be particularly useful to synthesize optically active cyclic seven membered enecarbamates and tetrasubstituted pyrrolidines.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.

This thesis is focused on the development of new palladium and copper- mediated reactions for functionalization of alkenes and propargylic alcohol derivatives. The synthetic utility of the 1,2-diborylated butadienes synthesized in one of these processes has also been demonstrated. We have developed an efficient procedure for the synthesis of allenyl boronates from propargylic carbonates and acetates. This was achieved by using a bimetallic system of palladium and copper or silver as co-catalyst. The reactions were performed under mild conditions for the synthesis of a variety of allenyl boronates. Furthermore, the synthesis of 1,2-diborylated butadienes was achieved with high diastereoselectivity from propargylic epoxides. The reactivity of the 1,2-diborylated butadienes with aldehydes was studied. It was found that the initial allylboration reaction proceeds via an allenylboronate intermediate. The allenylboronate reacts readily with an additional aldehyde to construct 2-ethynylbutane-1,4-diols with moderate to high diastereoselectivity. We have also studied the copper-mediated trifluoromethylation of propargylic halides and trifluoroacetates. It was also shown that a transfer of chirality occurred when an enantioenriched starting material was used. In the last part of the thesis, we have described a method for palladium-catalyzed functionalization of allylic C-H bonds for the selective synthesis of allylic silanes. The protocol only works under highly oxidative conditions which suggest a mechanism involving high oxidation state palladium intermediates. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 1: Accepted.</p>