The simplest Diels-Alder reactions are not: Endo -selective

There is a widespread perception that the high level of endo selectivity witnessed in many Diels-Alder reactions is an intrinsic feature of the transformation. In contrast to expectations based upon this existing belief, the first experimental Diels-Alder reactions of a novel, deuterium-labeled 1,3-butadiene with commonly used mono-substituted alkenic dienophiles (acrolein, methyl vinyl ketone, acrylic acid, methyl acrylate, acrylamide and acrylonitrile) reveal kinetic endo:exo ratios close to 1:1. Maleonitrile, butenolide, α-methylene γ-butyrolactone, and N-methylmaleimide behave differently, as does methyl vinyl ketone under Lewis acid catalysis. CBS-QB3 calculations incorporating solvent and temperature parameters give endo:exo product ratios that are in near quantitative agreement with these and earlier experimental findings. This work challenges the preconception of innate endo-selectivity by providing the first experimental evidence that the simplest Diels-Alder reactions are not endo-selective. Trends in behaviour are traced to steric and electronic effects in Diels-Alder transition structures, giving new insights into these fundamental processes.This work was supported by the Australian Research Council (DP160104322). MNP-R acknowledges that the computational component of this research was undertaken with the assistance of resources provided at the NCI National Facility through the National Computational Merit Allocation Scheme supported by the Australian Government

Theoretical Study of the [4+2] Cycloaddition Reaction of Trifluoroethylene with Five-membered Chalcogens Heterocyclic Compounds

[4+2] cycloaddition reaction has enormous significant in organic chemistry synthesis reactions and yet remains unexplored for the synthesis of fluorine-containing compounds. A density functional theory study of the stereo- and regioselectivity of the [4+2] cycloaddition reaction of trifluoroethylene with furan, thiophene, and selenophene was carried out in the gas phase. The B3LYP functional is used throughout in combination with 6-31G(d) basis set. The analysis of stationary points and the energetic parameters indicates that the reaction mechanism is concerted and confirms that the exo-adducts are thermodynamically and kinetically more favored than endo-adducts. The calculated branching ratio indicates that the exo-adducts have the higher percent yield than endoadducts and the yield of endo-adducts is increased only slightly on proceeding from furan, through thiophene, and onto selenophene. The analysis of the frontier molecular highest occupied molecular orbital (MO) and lowest unoccupied MO orbitals indicates that the exo-adducts are more stable due to their higher energy gab. The reaction energies were compared to the MP2/6-31G(d) and CCSD(T)/6-31G(d) calculations

A generic parallel combinatorial approach to Chiral Lewis acid catalyst discovery: application to the aza-Diels-Alder reaction

A generic parallel combinatorial method was used in order to attempt to develop new asymmetric processes for the aza-Diels-Alder reaction. Initially, an N-para-methoxyphenyl glyoxylate derived imine and its reactions with a variety of dienes was examined. Several new adducts were obtained, which included both "normal" "inverse" electron-demand aza-Diels-Alder products, and an acyclic product. These results strongly suggested the intervention of a stepwise addition-cyclisation mode of the reaction of diene with the imine. Later, new W-phosphorus imines were examined as dienophile substrates for aza-Diels-Alder reactions. The results of the reactions between these imines and a variety of dienes showed a reduced level of imine reactivity when compared to the N-para-methoxyphenyl C-carboxylate-derived system. Several new products were obtained and the results indicated a stepwise reaction process was in operation, due to the formation of other di-dehydro-piperidinone or acyclic ketone or aldehyde derivatives, hi this study, the first apparent N-phosphonyl imino-Diels-Alder reaction on such systems has been recorded. Screening reactions with different Lewis acids and chiral ligands produced no asymmetric induction, however, this system proved to be unreliable for monitoring by HPLC due to the presence of both cyclic and acyclic products

The use of ephedrine and camphor in asymmetric Diels-Alder reactions.

Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 1997.Due to the ever increasing demand for the production of enantiopure drugs and biologically active compounds, the study of asymmetric synthesis and the production of more efficient and cost effective methods of obtaining chiral compounds suggests that there are expanding opportunities for Organic Chemists in this field. Of the broad range of chiral technologies available today for the synthesis of even the most complex multi-centre chiral molecules, the use of chiral auxiliaries continues to remain an important means of obtaining single enantiomer chiral compounds. In this investigation, the imidazolidinone chiral auxiliary (i) was synthesised in order to determine its efficiency and ability to transfer chiral information in Diels-Alder cycloaddition reactions. The products of such reactions are extensively used in the synthesis of natural compounds and pharmaceutical drugs. The synthesis of the imidazolidinone auxiliary is described and mention is made of the fact that the starting materials are cheap and readily available in both enantiomeric forms. The pathway involves only a single reaction that is easily carried out in moderate yields of 60-65%. An adaptation of this auxiliary is the cyclohexyl derivative (ii) which was obtained in a single hydrogenation step of (i) in very high yields (98%). This was compared to the synthesis of the bornane-1O,2-sultam auxiliary (ii). Although the starting materials are also cheap and readily available, there are more reaction steps involved. The synthesis of the imidazolidinone auxiliary proved to be much more simple as well as more time and cost effective. The huge advantage of these auxiliaries is the fact that they are both crystalline which facilitates their purification and that of their derivatives. A possible deficiency of the imidazolidinone auxiliary and the bornane-1O,2-sultam auxiliary was the fact that substitution reaction yields with various a,b-unsaturated acyl chlorides were consistently low (<50%). A major by-product of the acylation reaction was a 'double-adduct' compound that severely affected the reaction yields. This was overcome by employing a new method of acylation developed during the course of this research. It involves the use of DABCO as base with reaction yields between 60 and 98%. In addition to this, reaction conditions were mild and work up procedures simple. The N-acylimidazolidinone auxiliary proved to be extremely successful in Diels-Alder reactions with cyclopentadiene With results equalling those obtained with the well known and highly publicised bornane-10,2-sultam auxiliary. The scope of the N-acylimidazolidinone auxiliary in these reactions included the use of a- and b- substituted dienophiles. Although reactions with a-methyl and b-methyl substituted dienophiles were successful, the auxiliary proved to be unreactive with b-phenyl and b,b-dimethyl substituted dienophiles. The scope of dienes used was extended to include the relatively less reactive isoprene and 2,3-dimethyl-l,3-butadiene. Only the former reacted successfully in Diels-Alder reactions with the N-acylimidazolidinone auxiliary. Crystallinity was imparted to all the products except for the cyclohexyl derivative whose cycloaddition adducts only solidified on standing. The Diels-Alder adducts were successfully cleaved under standard reaction conditions to give products with ee's ranging from 95:5 to 99:1. This investigation also includes the use of the tertiary amine, DABCO, as a catalyst in the Diels-Alder reaction with, specifically, the N-acryloylimidazolidinone chiral auxiliary. Most examples of Diels-Alder reactions involve the use of Lewis acids as a means of improving the rate and selectivity of Diels-Alder reactions. DABCO not only increased the reactivity of the N-acryloylimidazolidinone auxiliary towards cyclopentadiene, but selectivity was also observed. An explanation was put forward as to the mechanism of the reaction as well as to the source of selectivity. Selectivity was much more pronounced in Diels-Alder reactions with the N-acryloylimidazolidinone auxiliary than with the N-acryloylbornane-10,2-sultam auxiliary. It was predicted that DABCO catalysed reactions are amenable to large scale procedures. Due to the fact that the diastereomeric cycloadducts are easily purified by recrystallization or chromatography, and together with the practical advantages and mild reaction conditions this could render the DABCO methodology with the N-acryloylimidazolidinone auxiliary industrially viable

Investigation of novel thermal cyclisation reactions

[For full abstract, with illustrations, see pdf file]. Part 1. Concise Synthesis of Highly Substituted Isoquinolin-1(2H)-ones via IMDA The primary goal of this DPhil research project was to further investigate the mechanism of a novel thermally activated cyclisation reaction discovered within the Parsons’ research group. Through the synthesis and cyclisation of the substituted pyrrole rings 2.38a-c we have investigated the mechanism and increased the scope of the cyclisation reaction. We have also developed a robust route to advanced intermediate 2.10 in the synthesis of hymenialdisine 2.1. Part 2. Investigation and Development of a Novel Cascade Reaction The aim of this DPhil research project was to devise and execute a series of experiments to gain a better mechanistic understanding of the novel thermal cyclisation, discovered within the Parsons’ research group. To further investigate the mechanism and scope of the cyclisation, the model system 2.1 was initially selected. Through extensive modification and manipulation of the cyclisation precursor 2.1, we have increased the scope of the cyclisation and postulated a reaction pathway. During these studies remarkable transformation of ketone 2.81 to alkyne 2.82 was also observed. The repeatability of the above reactions was also investigated by synthesising various analogues

Total Synthesis of Ramonanins A–D

The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5-diaryl-3,4-dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels-Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6-31G(d) and M06-2X/6-31G(d) model chemistries.This work was supported by the Australian Research Council and a Marie Curie Career Integration Grant. M.N.P.-R. acknowledges that this research was undertaken with the assistance of resources provided at the NCI National Facility through the National Computational Merit Allocation Scheme supported by the Australian Government

Role of Cinchona Alkaloids in the Enantio- and Diastereoselective Synthesis of Axially Chiral Compounds

Asymmetric synthesis using organic catalysts has evolved since it was first realized and defined. Nowadays, it can be considered a valid alternative to transition metal catalysis for synthesizing chiral molecules. According to the literature, the number of asymmetric organocatalytic processes associated with atropisomer synthesis has rapidly increased over the past 10 years because organocatalysis addresses the challenges posed by the most widespread strategies used for preparing axially chiral molecules with satisfactory results. These strategies, useful to prepare a wide range of C–C, C–heteroatom, and N–N atropisomers, vary from kinetic resolution to direct arylation, desymmetrization, and central-to-axial chirality conversion. In this field, our contribution focuses on determining novel methods for synthesizing atropisomers, during which, in most cases, the construction of one or more stereogenic centers other than the stereogenic axis occurred. To efficiently address this challenge, we exploited the ability of catalysts based on a cinchona alkaloid scaffold to realize enantioselective organic transformations. Desymmetrization of N-(2-tert-butylphenyl) maleimides was one of the first strategies that we pursued for preparing C–N atropisomers. The main principle is based on the presence of a rotationally hindered C–N single bond owing to the presence of a large tert-butyl group. Following the peculiar reactivity of this type of substrate as a powerful electrophile and dienophile, we realized several transformations. First, we investigated the vinylogous Michael addition of 3-substituted cyclohexenones, where a stereogenic axis and two contiguous stereocenters were concomitantly and remotely formed and stereocontrolled using a primary amine catalyst. Subsequently, we realized desymmetrization via an organocatalytic Diels–Alder reaction of activated unsaturated ketones that enabled highly atropselective transformation with efficient diastereoselectivity, thereby simultaneously controlling four stereogenic elements. Employing chiral organic bases allowed us to realize efficient desymmetrizations using carbon nucleophiles, such as 1,3-dicarbonyl compounds, cyanoacetates, and oxindoles. These reactions, performed with different types of catalysts, highlighted the versatility of organocatalysis as a powerful strategy for atropselective desymmetrization of pro-axially chiral maleimides. Hereafter, we studied the Friedel–Crafts alkylation of naphthols with indenones, a powerful method for enantioselective synthesis of conformationally restricted diastereoisomeric indanones. We realized the first axially chiral selective Knoevenagel condensation using cinchona alkaloid primary amine as the catalyst. This reaction provided a powerful method to access enantioenriched olefins containing the oxindole core. Subsequently, we initiated an intense program for the computational investigation of the reaction mechanism of our atropselective processes. An understanding of the catalytic activity for vinylogous atropselective desymmetrization as well as of the role played by the acidic cocatalyst used for the experimental work was achieved. Recently, we have garnered interest in the novel frontiers of atropselective synthesis. As observed in recent publications, there is considerable interest in the development of methods for preparing N–N atropisomers, an emerging topic in the field of atropselective synthesis. We focused on the synthesis of hydrazide atropisomers by developing a one-pot sequential catalysis protocol based on two sequential organocatalytic reactions that provided high stereocontrol of two contiguous stereogenic elements

Synthesis of model cytochalasan precursors and in vitro studies of their activities

Cytochalasans are one type of PKS-NRPS secondary metabolites. The tailoring steps involved in cytochalasan biosynthesis are almost clear, but the formation of the isoindolone core is still mysterious. The ACE1 metabolite probably belongs to the cytochalasan family based on the biosynthetic gene cluster (BGC) analysis, even though the structure is not yet elucidated. Heterologous expression of ace1 (PKS-NRPS) and rap1 (trans-ER) in A. oryzae produced an unexpected alcohol, which is unlikely to undergo further Knoevenagel reaction. Therefore it is deduced to be a shunt metabolite during heterologous expression. To investigate the biosynthesis of the cytochalasan skeleton including reductive release, putative Knoevenagel condensation and Diels-Alder reaction, three model compounds mimicking the ACE1 metabolite precursor were designed, prepared and applied for in vitro assays. Model A was designed and synthesized for over-reduction investigation. In vitro assays confirmed that model A can be reduced to the corresponding primary alcohol by A. oryzae cell free extract. This indicates that the alcohol is a shunt metabolite and A. oryzae is not a suitable host for cytochalasan heterologous expression. Model B was designed and prepared to study Knoevenagel condensation. In vitro assays with model B suggested model B can possibly form pyrrolinone spontaneously in buffer, while pyrrolinone was converted rapidly to alcohols. However, no enzyme activity was observed. Besides, pyrrolinone tautomerism was further investigated by comparing tautomerized pyrrolinone and non-tautomerised pyrrolinone. From NMR and UV analysis, it is confirmed that pyrrolinones tautomerises and are no longer competitive for the following Diels-Alder reaction. Model C was designed for both Knoevenagel condensation and Diels-Alder reaction tests. In vitro Assays showed that pyrrolinone was formed spontaneously, further confirming the Knoevenagel condensation is spontaneous. But its corresponding pyrrolinone also tautomerised and is no longer suitable for the following Diels-Alder reaction

Synthesizing Self-Healing and Recyclable Silicones Using the Diels-Alder Reaction as a Cross-Linker: Investigation of Various Dienes and Dienophile Systems

This thesis focuses on the synthesis of recyclable and self-healing polysiloxane elastomer networks. These features were achieved through the use of thermally reversible Diels-Alder (DA) and retro-Diels-Alder (rDA) reactions. In this work, for the model system, two different dienes (3 and 8) and six dienophile were explored, of which five of the dienophiles are commercially available and one of them was synthesized in the lab (13) to produce a series of model DA adduct. Model systems consisting of diene-functionalized trisiloxanes and bismaleimides as dienophiles were utilized to develop a fundamental understanding of how the electronic differences in the coupling systems would influence the efficiency of the overall reaction. Then for the elastomers, three different methylhydrosiloxane-dimethylsiloxane copolymer, trimethylsiloxane terminated (PDMS) with different molecular weights and Si-H group mole percentages [32 a = 3-4% Si-H and 13000 g/mol; 32 b = 7-9% Si-H and 5500-6500 g/mol; 32 c = 25-30% Si-H and 2000-2600 g/mol] were used and functionalized with two different dienes (3 and 8) to produce six polymeric diene systems (33 a, 33 b, 33 c, 34 a, 34 b and 34 c). After analyzing the model systems, the optimal temperature for adduct formation was determined to be between 60 °C – 70 °C, while the rDA reactions occur were found to occur between 90 °C and 110 °C , depending on the system. The tensile strengths of the elastomer systems correlated well with the cross-link densities of individual elastomers (elastomers were elongated between 0.3 cm and 2.54 cm). Furthermore, the hardness of the elastomers also correlated with the cross-link density of the elastomer (Shore 00 values ranged from 32 to 8 ). However, all of the elastomers displayed a decrease in their Shore 00 values after being damaged and healed. Of particular note in this study are elastomers 35 b and 35 c. Not only were these the only examples of translucent and colourless materials, the elastomers fully cured at room temperature in only 5 h. After mechanical damage the elastomers were heated to 80 °C to induce mobility in the polymer chains, complete healing of the mechanical damage was observed to occur in approximately 3 min and upon cooling to room temperature it cured and got solid again

Synthetic approach to the novel cholecystokinin (CCK)-B receptor antagonist tetronothiodin

The thesis consists first of an introduction discussing CCK-receptor antagonists and the role tetronothiodin plays. There is a section on the isolation and characterisation of the tetronothiodin structure. This leads to a retrosynthesis of the compound and the synthetic plan towards forming the oxaspirobicyclic moiety. The introduction includes the initial ideas for the construction of this subunit, with analogous subunits in the literature being discussed. A brief review of the likely chemistry is discussed. The second chapter is the results and discussion section, beginning with the formation of the Diels–Alder precursors and the chemistry used to form a suitably functionalised cyclohexene rings with the aim of forming the cyclohexenone. [Continues.