Chiral dendralenes for rapid access to enantiomerically pure polycycles.
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Journal Article↗
Biomedical subjects
Michael S Sherburn
Publications and source records attributed to Michael S Sherburn.
Intramolecular Diels-Alder reactions of ester linked 1,3,9-decatrienes: cis/trans selectivity in thermal and Lewis acid promoted reactions of ethylene-tethered and benzo-tethered systems.
High cis (i.e., endo) diastereoselectivities are witnessed in heat-promoted intramolecular Diels-Alder (IMDA) reactions of ethylene-tethered hexadienyl acrylates. The cis stereoselectivity is improved by promotion with Et2AlCl. The first examples of Et2AlCl catalyzed intramolecular Diels-Alder reactions of ester-activated dienophiles are reported. In contrast, the corresponding benzo-tethered hexadienyl acrylates undergo moderately trans (i.e., exo) selective IMDA reactions. Very high trans stereoselection is obtained upon promotion with ATPH. The outcomes of these reactions are essentially insensitive to dienophile (C10) geometry and substitution. DFT (B3LYP/6-31+G(d)) computed cis/trans product distributions-based on Boltzmann transition structure populations-are in good agreement with the experimental results. These computational investigations provide useful insights into the origins of stereoselection in these systems. The stereoselectivity exhibited by the ethylene-tethered hexadienyl acrylates is ascribed to stabilizing secondary orbital interactions at play in the cis-transition structures (TSs). In the benzo-tethered series, this effect is overridden by stabilizing pi-conjugative interactions, between the benzo moiety and the 1,3-diene component, which are stronger in trans TSs, compared to the cis TSs. The computed TS geometries generally exhibit advanced peripheral bond forming asynchronicity, with the tether carbonyl group in conjugation with the dienophile. Such TS features significantly weaken the stereodirecting influence of terminal dienophile substituents.
Acids↗
Self-assembly of supramolecular platinum complexes with bis-4-pyridyl cavitands.
The design and self-assembly of six new supramolecular complexes (four triangles and two 2+2 assemblies) are described. These assemblies incorporate two new bispyridyl cavitand building blocks and were prepared in excellent yields (85-95%). The assemblies and building blocks were characterized with multinuclear NMR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis. Isotopically resolved mass spectrometry along with NMR data confirms the existence of the six assemblies.
Ethers, Cyclic↗
Enhanced stereocontrol in Diels-Alder reactions of chiral dienols.
This combined experimental-computational investigation demonstrates that the presence of a removable bromine substituent on a diene leads to complete pi-diastereofacial and endo/exo stereoselection in both intermolecular and intramolecular Diels-Alder reactions. The influence of the bromine upon stereoselectivity is dramatic: the cycloaddition of nonbrominated precursor 18E, for example, gives four diastereomeric products in a 55:13:16:16 ratio; the bromine-containing analogue gives one stereoisomer within the limits of detection. The examination of B3LYP/6-31+G(d) transition structures allows an interpretation of these experimental findings. A method for the completely stereoselective synthesis of complimentary diastereomeric products (30Z and 31Z) from the same simple starting materials (28 and 2) is reported. Discrepancies between calculation and experiment in an earlier investigation into the Diels-Alder reaction are explained.
Journal Article↗
On the origin of cis/trans stereoselectivity in intramolecular Diels-Alder reactions of substituted pentadienyl acrylates: a comprehensive density functional study.
[structures: see text] A gas-phase B3LYP/6-31+G(d) study of substituent effects on the stereochemistry of both intramolecular Diels-Alder (IMDA) reactions of 9-E- and 9-Z-substituted pentadienyl acrylates and intermolecular Diels-Alder (DA) reactions between butadiene and monosubstituted alkenes and 3-substituted acrylates is reported and involves the calculation of 230 transition structures. It was found that, although exo ("anti-Alder") addition of monosubstituted ethenes to butadiene is the norm, Alder endo selectivity is more widely predicted for 3-substituted methyl acrylate dienophiles, and this was explained in terms of secondary orbital interactions (SOIs). Whereas cis/trans selectivity for IMDA reactions involving 9-E-substituted pentadienyl acrylates generally follows the normal pattern found for the corresponding intermolecular DA reactions, the 9-Z-substituted stereoisomers generally displayed trans selectivity that was much stronger than can be attributed to effects of the isolated substituent. This is strikingly so with unsaturated electron-withdrawing substituents whose endo selectivities, displayed in intermolecular DA reactions, are reversed in the IMDA reactions of pentadienyl acrylates. The origin of this anomalous Z-effect is explained in terms of the twist-mode asynchronicity concept of Brown and Houk. These ideas are used to explain the stereochemical outcomes of IMDA reactions of other triene systems.
Journal Article↗
Practical synthesis and Diels-Alder chemistry of [4]dendralene.
Spectacular new atom efficient domino cycloaddition sequences involving [4]dendralene, the simplest cross-conjugated tetraene, are reported. Up to eight stereocenters, three new rings, and six C-C bonds are generated in one synthetic operation. The site selectivity of dienophile addition to cross-conjugated trienes and tetraenes is controlled with a simple Lewis acid.
Journal Article↗
Intramolecular Diels-Alder reactions of ester-linked 1,3,8-nonatrienes.
[structures: see text] Penta-1,3-dienyl acrylates undergo kinetically controlled intramolecular Diels-Alder (IMDA) reactions and DFT calculations (B3LYP/6-31+G(d)) predict stereoselectivities that are in very good agreement with the experimental values. The nature of the diene C1 substituent has virtually no influence upon reactivity or trans/cis-stereoselectivity whereas terminal C9 dienophile substituents have a substantial effect on both the reactivity and stereoselectivity of these IMDA reactions. The TSs highlight contributions from strain in the developing tether-containing ring, and steric and electronic effects between tether and dienophile substituents, thus providing insight into the origins of IMDA reactivity and stereoselectivity.
Journal Article↗
Practical synthesis and guest-guest communication in multi-hemicarceplexes.
Single molecule hosts carrying three separately encapsulated guests are prepared in a seven step sequence in high overall yields.
Journal Article↗
Single and double Suzuki-Miyaura couplings with symmetric dihalobenzenes.
[reaction: see text] m- or p-Diiodobenzene undergoes selective double coupling reactions with arylboronic acids and esters. Selectivity for double coupling over single coupling is remarkably strong: even with a diiodobenzene:monoboronic acid ratio of 10:1, the products of double coupling are formed in good yields. Steric hindrance and electronic influences of the boronic acid or ester, and reaction conditions do not appear to impact significantly upon the outcome of the reaction. In contrast, m- and p-dibromobenzenes undergo single couplings with aryl boronic acids with high selectivity.
Journal Article↗
Allylic stereocontrol of the intramolecular Diels-Alder reaction.
The stereochemical outcome of the intramolecular Diels-Alder reaction of ester-linked 1,3,8-nonatrienes can be controlled by substituents about a stereogenic center attached to C1. The scope and limitations of this approach have been investigated, with variation in substrate structure about the allylic stereocenter and the dienophile. The stereochemical outcomes of these reactions are explained by reference to B3 LYP/6-31G(d) transition structures. New insights into the conformational preferences of allylic alcohol derivatives are reported, results which allow an explanation of the differing levels of pi-diastereofacial selectivity and cis/trans (i.e. endo/exo) selectivity from the reaction.
Ascorbic Acid↗
On the Diels-Alder reactions of pentadienyl maleates and citraconates.
Reactions between conjugated dienols and maleic anhydride provide either cis-fused or trans-fused bicyclic products as major products, depending upon how the reaction is carried out. Simply mixing the two reactants together generally leads to cis-fused lactone acids in thermal reactions which proceed viaintermolecular Diels-Alder reaction followed by intramolecular esterification. Pre-forming the maleate half ester derivative followed by heating affords predominantly trans-fused lactone acids in good yields by way of an intramolecular Diels-Alder (IMDA) reaction. Sorbyl citraconate half esters undergo a rapid thermolytic fragmentation in refluxing toluene to form the dienol and citraconic anhydride. The resulting diene-dienophile pair undergo an intermolecular cycloaddition followed by a rapid intramolecular esterification to give cis-fused bicyclic lactone acids as major products. The IMDA reaction of citraconic half esters is sufficiently rapid in DMSO to dominate over fragmentation: the exo-cycloadduct is formed almost exclusively. Nine literature reports of endo-selective IMDA reactions of triene acids are erroneous; the cycloadditions proceed in an intermolecular manner.
Journal Article↗
Double diels-alder reactions of linear conjugated tetraenes.
[reaction: see text] Linear conjugated tetraenes are shown to participate effectively as bis-dienes in sequences involving either two intermolecular Diels-Alder reactions or an intramolecular followed by an intermolecular Diels-Alder reaction. Thus, simple tetraenol 1 is transformed into tetracyclic products 5, 6, and 9 in high yielding and highly stereoselective sequences with maleic anhydride involving the formation of three rings, four C-C bonds and one C-O bond, and eight stereocenters. In the latter case, the one-pot reaction protocol is very simple, and furnishes a single diastereoisomeric product in essentially quantitative yield. Linear conjugated tetraenes exhibit complete terminal site selectivity in reactions with dienophiles and computational investigations reveal that two discrete pi-conjugative interactions are the origin of this unexpected reactivity. B3LYP/6-31G(d) transition structures also allow an explanation of unexpectedly high pi-diastereofacial selectivities witnessed during these transformations, through the identification of preferred C1-C diene conformations and nonbonded interactions. These new experimental and computational findings encourage the use of linear conjugated polyenes in domino sequences.
Journal Article↗
Superbowl container molecules.
The design, chemical synthesis, guest binding, and self-assembly of tureen-shaped container molecules is presented. With a large noncollapsible interior and five external binding sites, each superbowl container host is shown to bind up to nine guest molecules in well-defined locations.
Calixarenes↗
Radical carboxyarylation approach to lignans. Total synthesis of (-)-arctigenin, (-)-matairesinol, and related natural products.
[reaction: see text] Total syntheses of seven biologically important lignan natural products, including (-)-arctigenin, (-)-matairesinol, and (-)-alpha-conidendrin, by way of a highly stereoselective domino radical sequence is presented. The reported stereochemistry of the natural product 7-hydroxyarctigenin is shown to be erroneous; a diastereoisomeric structure is assigned to the natural product.
Antineoplastic Agents↗
The intramolecular carboxyarylation approach to podophyllotoxin.
Since 1960, only seven plant-derived anticancer drugs have received FDA approval for commercial production. Two are semisynthetic derivatives of podophyllotoxin. This paper describes concise, highly convergent, and conceptually novel approaches to (-)-podophyllotoxin and its enantiomer. These highly convergent syntheses feature a late-stage domino radical reaction to install the lactone ring and the pendant trimethoxyphenyl group.
Podophyllotoxin↗
IMDA-radical cyclization approach to (+)-himbacine.
[reaction: see text] A formal total synthesis of the selective muscarinic receptor antagonist himbacine is presented. Key C-C bond-forming steps include an intramolecular Diels-Alder reaction, Stille coupling reactions, and a 6-exo-trig acyl radical cyclization to a conjugated enyne. An unexpected secondary alcohol to chloride conversion is witnessed during attempted thionocarbonate formation.
Alkaloids↗
On the endo/exo stereoselectivity of intramolecular Diels-Alder reactions of hexadienylacrylates: an interesting failure of density functional theory.
[formula: see text] A combined experimental and computational study of endo/exo stereoselectivity in a series of IMDA reactions of hexadienylacrylates has found that DFT makes erroneous predictions when the endo and exo transition states possess differing degrees of conjugation. These problems are overcome by carrying out calculations at the MP2 level of theory, which gives remarkably accurate Boltzmann distributions of products. These findings are used to predict ways to obtain either endo- or exo-cycloadducts exclusively.
Journal Article↗
Cavitand boronic acids mediate highly selective fructose transport.
The synthesis sugar-transport properties of a family of five cavitand rim-appended boronic acids are reported. These conformationally rigid compounds are not observed to leach out of lipophilic membranes, and they exhibit unprecedented fructose to glucose transport selectivities and give higher fluxes than other neutral boronic acids. These properties make the cavitand boronic acids the best artificial fructose transporters described thus far. [structure: see text]
Boronic Acids↗