ABSTRACT: The crystal structure of the title compound, C(34)H(54)N(2)O(4), has been solved in order to prove the relative and absolute chirality of the newly-formed stereocentres which were established using an asymmetric Diels-Alder reaction at an earlier stage in the synthesis. This unprecedented stable dialdimine contains a 14-membered ring and was obtained as the minor diastereoisomer in the Diels-Alder reaction. The absolute stereochemistry of the stereocentres of the acetal functionality was known to be R based on the use of a chiral (R)-tris-ubstituted dienophile derived from enanti-opure (S)-glyceraldehyde. The assignment of the configuration in the dienophile and the title di-aldimine differs from (S)-glyceraldehyde due to a change in the priority order of the substituents. The crystal structure establishes the presence of six stereocentres all attributed to be R. The 14-membered ring contains two aldimine bonds [C-N = 1.258?(2) and 1.259?(2)?Å]. It adopts a similar conformation to that proposed for trans-trans-cyclo-tetra-deca-1,8-dienes.
Project description:Polypropionates-motifs with alternating methyl and hydroxy groups-are important segments of many natural products possessing high bioactivity and therapeutic value. Synthetic access to these structures remains an area of intensive interest, focusing on the establishment of the contiguous stereocentres and a desire for operational simplicity. Here we report an efficient strategy for the stereoselective assembly of polypropionates with three or four stereocentres through a three-step relay process that include Diels-Alder reaction, silylenol ether hydrolysis and Baeyer-Villiger oxidation. The stereochemistry and functionality of the resulting polypropionates depend on the substitution pattern of the diene and dienophile substrates of the Diels-Alder cycloaddition. More importantly, the relay sequence is effectively performed in one pot, and the product could potentially undergo the same sequence for further elaboration. Finally, the C1-C9 segment of the macrolide etnangien is constructed with four of the six stereogenic centres established using the relay sequence.Polypropionates are present in many natural products possessing high bioactivity and therapeutic value. Here the authors show a strategy for the stereoselective assembly of polypropionates with three or four stereocentres through a process that includes a Diels-Alder reaction, silylenol ether hydrolysis and Baeyer-Villiger oxidation.
Project description:The Diels-Alder reaction is a useful tool for generating functionalized chiral molecules through the concerted cycloaddition of dienes and dienophiles leading to six-membered rings. Traditionally, the selective predictions of the products rely heavily on consideration of the secondary orbital interactions that stabilize the endo pathway. However, there remain some basic examples defying this notion and produce the exo-isomer as major product. Here we systematically evaluated of the structural features driving exo selectivity in thermal normal-electron-demand Diels-Alder reactions. Substitution at the Cβ position and the size and electronegativity of the electron-withdrawing group of the dienophile are contributing factors. Experimental and computational studies both point toward the steric and electrostatic forces between the substituents in both the diene and the dienophile that increase the likelihood of the exo pathway. For these substrates, the dominance of the endo pathway is reduced by transition state distortions and poor structural alignments of the reacting partners. We also noted the tilt of the dienophile with respect to the diene causing steric strain on the functionalities at the more advanced bond forming carbon-carbon position of the endo transition state. Insights into such factors may benefit synthetic planning and asserting control over this important named reaction.
Project description:In the classic Diels-Alder [4?+?2] cycloaddition reaction, the overall degree of unsaturation (or oxidation state) of the 4? (diene) and 2? (dienophile) pairs of reactants dictates the oxidation state of the newly formed six-membered carbocycle. For example, in the classic Diels-Alder reaction, butadiene and ethylene combine to produce cyclohexene. More recent developments include variants in which the number of hydrogen atoms in the reactant pair and in the resulting product is reduced by, for example, four in the tetradehydro-Diels-Alder (TDDA) and by six in the hexadehydro-Diels-Alder (HDDA) reactions. Any oxidation state higher than tetradehydro (that is, lacking more than four hydrogens) leads to the production of a reactive intermediate that is more highly oxidized than benzene. This increases the power of the overall process substantially, because trapping of the reactive intermediate can be used to increase the structural complexity of the final product in a controllable and versatile manner. Here we report an unprecedented overall 4??+?2? cycloaddition reaction that generates a different, highly reactive intermediate known as an ?,3-dehydrotoluene. This species is in the same oxidation state as a benzyne. Like benzynes, ?,3-dehydrotoluenes can be captured by various trapping agents to produce structurally diverse products that are complementary to those arising from the HDDA process. We call this new cycloisomerization process a pentadehydro-Diels-Alder (PDDA) reaction-a nomenclature chosen for chemical taxonomic reasons rather than mechanistic ones. In addition to alkynes, nitriles (RC?N), although non-participants in aza-HDDA reactions, readily function as the 2? component in PDDA cyclizations to produce, via trapping of the ?,3-(5-aza)dehydrotoluene intermediates, pyridine-containing products.
Project description:Cyclobutenone was employed as a dienophile in Diels-Alder cycloadditions, provide diverse and complex cycloadducts in good yields. Experimental outcomes indicated cyclobutenone to be more reactive than either cyclopentenone or cyclohexenone. In addition, cycloadducts bearing a strained cyclobutanone moiety were able to undergo regioselective ring expansions to produce corresponding cyclopentanones, lactones, and lactams, which are otherwise difficultly obtained by direct Diels-Alder reactions.
Project description:Novel routes to the naturally occurring indole alkaloid cycloclavine and its unnatural C(5)-epimer are described. Key features include the rapid construction of the heterocyclic core segments by two Diels-Alder reactions. An indole annulation was accomplished by a late-stage intramolecular Diels-Alder furan cycloaddition, and a methylenecyclopropane dienophile was used for a stereoselective intramolecular [4 + 2] cycloaddition to give the cyclopropa[c]indoline building block present in cycloclavine.
Project description:The analysis of binding interactions between small molecules and biopolymers is important for understanding biological processes. While fluorescence correlation spectroscopy (FCS) requires fluorescence labeling on the small molecule, which often interferes with binding, in microscale thermophoresis (MST) the label can be placed on the biopolymer. Ribozymes have not been analyzed by MST so far. The Diels-Alderase ribozyme (DAse) is a true catalyst, facilitating the Diels-Alder reaction between two free small substrates, anthracene dienes, and maleimide dienophiles. Despite high efforts, the determination of the dissociation constant (KD) of maleimide dienophiles to the DAse by FCS has been unsuccessful. Here, we determined the binding interactions of the DAse to its substrates and the Diels-Alder product using MST. The results supported a positive cooperativity for substrate binding to the DAse. By varying the temperature, we furthermore studied the thermodynamics of dienophile dissociation. The entropic contribution was found to be the energetic driving force for the binding of the dienophile to the DAse.
Project description:A Diels-Alder based route to trans-fused angularly functionalized bicyclic structures has been developed. This transformation features the use of a tetrasubstituted dienophile in the cycloaddition step.
Project description:The Lewis acid(LA)-catalyzed Diels-Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled-cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I2 <SnCl4 <TiCl4 <ZnCl2 <BF3 <AlCl3 . Emerging from our activation strain and Kohn-Sham molecular orbital bonding analysis was an unprecedented finding, namely that the LAs accelerate the Diels-Alder reaction by a diminished Pauli repulsion between the ?-electron systems of the diene and dienophile. Our results oppose the widely accepted view that LAs catalyze the Diels-Alder reaction by enhancing the donor-acceptor [HOMOdiene -LUMOdienophile ] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.
Project description:A series of eight new 5-aryl-benzo[f][1,7]naphthyridines were synthesized in 17 to 64% overall yields via an improved MW-assisted cascade-like one pot process (Ugi?three component reaction/intramolecular aza-Diels-Alder cycloaddition) coupled to an aromatization process from tri-functional dienophile-containing ester-anilines, substituted benzaldehydes and the chain-ring tautomerizable 2-isocyano-1-morpholino-3-phenylpropan-1-one as starting reagents, under mild conditions. The doubly activated dienophile and the aza-diene functionalities of the eight new Ugi-adducts were exploited to perform an in situ aza-Diels-Alder cycloaddition/aromatization (dehydration/oxidation) process, toward the complex polysubstituted 5-aryl-polyheterocycles, which could be taken as starting point for further SAR studies because the benzo[f][1,7]naphthyridine is the core of various bioactive products. It is relevant to emphasize that the synthesis or isolation of benzo[f][1,7]naphthyridines containing a substituted aromatic ring in the C-5 position, has not been published before.
Project description:[reaction: see text] A direct synthesis of the alpha-hydroxyaldehyde exo-5, a precursor of the exo-spirotetronate subunit of the quartromicins, was achieved through an exo-selective Lewis acid-catalyzed Diels-Alder reaction of dienophile 12a and diene 1.