Co-reporter:Jie S. Zhu, Jung-Ho Son, Andrew P. Teuthorn, Makhluf J. Haddadin, Mark J. Kurth, and Dean J. Tantillo
The Journal of Organic Chemistry October 20, 2017 Volume 82(Issue 20) pp:10875-10875
Publication Date(Web):September 19, 2017
DOI:10.1021/acs.joc.7b01521
The discovery of a new variation on the Davis–Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its expected reactivity—a potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described.
Co-reporter:Stephanie R. Hare, Ryan P. Pemberton, and Dean J. Tantillo
Journal of the American Chemical Society June 7, 2017 Volume 139(Issue 22) pp:7485-7485
Publication Date(Web):May 15, 2017
DOI:10.1021/jacs.7b01042
Dynamics calculations are described for carbocation rearrangements involving product-forming pathways with post-transition-state bifurcations. We show that noncovalent interactions with associated benzene rings (a simple model of aromatic amino acid side chains) can switch inherent dynamical tendencies for competing modes of disrotation, establishing that meaningful changes in dynamically controlled product selectivity can be achieved with few weak noncovalent interactions.
Co-reporter:Sidney M. Wilkerson-Hill, Diana Yu, Phillip P. Painter, Ethan L. Fisher, Dean J. Tantillo, Richmond Sarpong, and Jason E. Hein
Journal of the American Chemical Society August 2, 2017 Volume 139(Issue 30) pp:10569-10569
Publication Date(Web):July 6, 2017
DOI:10.1021/jacs.7b06007
A mechanistic study of a new heterocycloisomerization reaction that forms annulated aminopyrroles is presented. Density functional theory calculations and kinetic studies suggest the reaction is catalyzed by trace copper salts and that a Z- to E-hydrazone isomerization occurs through an enehydrazine intermediate before the rate-determining cyclization of the hydrazone onto the alkyne group. The aminopyrrole products are obtained in 36–93% isolated yield depending on the nature of the alkynyl substituent. A new automated sampling technique was developed to obtain robust mechanistic data.
Co-reporter:Christina H. McCulley, Michael J. Geier, Brandi M. Hudson, Michel R. Gagné, and Dean J. Tantillo
Journal of the American Chemical Society August 16, 2017 Volume 139(Issue 32) pp:11158-11158
Publication Date(Web):July 18, 2017
DOI:10.1021/jacs.7b05381
Results of kinetic experiments and quantum chemical computations on a series of platinum-promoted polycyclization reactions are described. Analyses of these results reveal a reactivity model that reaches beyond the energetics of the cascade itself, incorporating an ensemble of pre-cyclization conformations of the platinum–alkene reactant complex, only a subset of which are productive for bi- (or larger) cyclization and lead to products. Similarities and differences between this scenario, including reaction coordinates for polycyclization, for platinum- and enzyme-promoted polycyclization reactions are highlighted.
Co-reporter:Young J. Hong and Dean J. Tantillo
The Journal of Organic Chemistry April 7, 2017 Volume 82(Issue 7) pp:3957-3957
Publication Date(Web):March 9, 2017
DOI:10.1021/acs.joc.7b00187
Results from density functional theory computations indicate that a 1,4-alkyl shift proposed as part of the carbocation cyclization/rearrangement leading to ledol, viridiflorol, and related sesquiterpenes is not energetically viable. Instead, a previously proposed mechanism that avoids such a shift is greatly preferred.
Co-reporter: Dean J. Tantillo
Angewandte Chemie 2017 Volume 129(Issue 34) pp:10172-10178
Publication Date(Web):2017/08/14
DOI:10.1002/ange.201702363
AbstractIn diesem Kurzaufsatz wird die Bedeutung der inhärenten Substratreaktivität von Terpen-Synthasen diskutiert. Der Fokus liegt auf neuen experimentellen Validierungen von Vorhersagen, die anhand von Berechnungen der Reaktivität von Carbokationen in der Gasphase getroffen wurden.
Co-reporter: Dean J. Tantillo
Angewandte Chemie International Edition 2017 Volume 56(Issue 34) pp:10040-10045
Publication Date(Web):2017/08/14
DOI:10.1002/anie.201702363
AbstractThe importance of inherent substrate reactivity for terpene synthase enzymes is discussed, with a focus on recent experimental tests of predictions derived from computations on gas-phase reactivity of carbocations.
Co-reporter:Stephanie R. Hare, Jessica M. Farnham, Dean J. Tantillo
Tetrahedron 2017 Volume 73, Issue 29(Issue 29) pp:
Publication Date(Web):20 July 2017
DOI:10.1016/j.tet.2016.11.031
Density functional theory calculations were carried out in order to determine the viability of putative mechanistic pathways for formation of the diterpenoid (+)-chatancin. It was found that a cycloaddition involving a pyrylium ion would have a lower energetic barrier than previously proposed cycloadditions involving a 2H-pyran or furan. All three reactions are predicted to be concerted.Download high-res image (142KB)Download full-size image
Co-reporter:Florian Bartels;Young J. Hong;Daijiro Ueda;Manuela Weber;Tsutomu Sato;Mathias Christmann
Chemical Science (2010-Present) 2017 vol. 8(Issue 12) pp:8285-8290
Publication Date(Web):2017/11/20
DOI:10.1039/C7SC03903D
The first chemical synthesis of pentacyclic onocerane triterpenoids has been achieved. A putative biomimetic tricyclization cascade is employed to forge a fused decalin-/oxepane ring system. The synthetic route proceeds to (+)-cupacinoxepin in seven steps and to (+)-onoceranoxide in eight steps in the longest linear sequence, when starting from geranyl chloride and (+)-sclareolide. The bioinspired epoxypolyene cyclization is supported by computational and enzymatic studies.
Co-reporter:Stephanie R. Hare
Chemical Science (2010-Present) 2017 vol. 8(Issue 2) pp:1442-1449
Publication Date(Web):2017/01/30
DOI:10.1039/C6SC03745C
Byproducts of chemical reactions are generally thought to result from the competition between two reaction pathways, each with its own rate-determining transition state structure. We show here, however, that pathways with a single transition state structure followed by a post-transition state bifurcation may also be a source of undesired products, especially those whose appearance is unexpected. The viability of this scenario for intramolecular C–H insertion reactions affording β-lactones via Rh-carbenoid intermediates is assessed through quantum chemical calculations on potential energy surfaces and quasi-classical molecular dynamics simulations. It appears that, in these cases, the rhodium catalyst is to blame for the accessibility of a second, unintended, pathway following the transition state structure for β-lactone formation that leads to fragmentation to a ketene and carbonyl compound. If an unexpected product is formed via a post-transition state bifurcation, conventional strategies for suppressing its formation are unlikely to succeed. Guidelines for recognizing the presence of a post-transition state bifurcation are described here, along with hints at means for controlling product distributions.
Co-reporter:Mikail E. Abbasov;Brandi M. Hudson;Daniel Romo
Chemical Science (2010-Present) 2017 vol. 8(Issue 2) pp:1511-1524
Publication Date(Web):2017/01/30
DOI:10.1039/C6SC04273B
Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels–Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Brønsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol–Brønsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects.
Co-reporter:Mikail E. Abbasov;Brandi M. Hudson;Weixu Kong;Daniel Romo
Organic & Biomolecular Chemistry 2017 vol. 15(Issue 15) pp:3179-3183
Publication Date(Web):2017/04/11
DOI:10.1039/C6OB02738E
α,β-Unsaturated acylammonium salts are useful dienophiles enabling highly enantioselective and stereodivergent Diels-Alder-initiated organocascades with furan-based dienes. Complex polycyclic systems can thus be obtained from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe the use of furan-based dienes bearing pendant sulfonamides leading to the generation of oxa-bridged, trans-fused tricyclic γ-lactams. This process constitutes the first highly enantio- and diastereoselective, organocatalytic Diels-Alder cycloadditions with these typically problematic dienes due to their reversibility. Computational studies suggest that the high diastereoselectivity with these furan dienes may be due to a reversible Diels-Alder cycloaddition for the endo adducts. In addition, the utility of this methodology is demonstrated through a concise approach to a core structure with similarity to the natural product isatisine A and a nonpeptidyl ghrelin-receptor inverse agonist.
Co-reporter:Selina C. Wang
Organic & Biomolecular Chemistry 2017 vol. 15(Issue 9) pp:1976-1979
Publication Date(Web):2017/03/01
DOI:10.1039/C6OB02300B
The results of density functional theory calculations on thiyl radical-promoted polycyclization to form dodecahedrane are described. On the basis of these results, the proposed polycyclization is predicted to be both highly exergonic and fast. These results showcase the potential power of radical polycyclization reactions in constructing complex molecular architectures.
Co-reporter:Dean J. Tantillo
Accounts of Chemical Research 2016 Volume 49(Issue 4) pp:741
Publication Date(Web):April 6, 2016
DOI:10.1021/acs.accounts.6b00029
Catalysis is common. Rational catalyst design, however, is at the frontier of chemical science. Although the histories of physical organic and synthetic organic chemistry boast key chapters involving [3s,3s] sigmatropic shifts, catalysis of these reactions is much less common than catalysis of ostensibly more complex processes. The comparative dearth of catalysts for sigmatropic shifts is perhaps a result of the perception that transition state structures for these reactions, like their reactants, are nonpolar and therefore not amenable to selective stabilization and its associated barrier lowering. However, as demonstrated in this Account, transition state structures for [3s,3s] sigmatropic shifts can in fact have charge distributions that differ significantly from those of reactants, even for hydrocarbon substrates, allowing for barriers to be decreased and rates increased. In some cases, differences in charge distribution result from the inclusion of heteroatoms at specific positions in reactants, but in other cases differences are actually induced by catalysts. Perhaps surprisingly, strategies for complexation of transition state structures that remain nonpolar are also possible. In general, the strategies for catalysis employed can be characterized as involving either mechanistic intervention, where a catalyst induces a change from the concerted mechanism expected for a [3s,3s] sigmatropic shift to a multistep process (cutting the transformation into halves or smaller pieces) whose overall barrier is decreased relative to the concerted process, or transition state complexation, where a catalyst simply binds (holds) more tightly to the transition state structure for a [3s,3s] sigmatropic shift than to the reactant, leading to a lower barrier in the presence of the catalyst. Both of these strategies can be considered to be biomimetic in that enzymes frequently induce multistep processes and utilize selective transition state stabilization for the steps involved. In addition, transition state complexation was the principle around which catalytic antibodies were originally designed. The field of catalysis of sigmatropic shifts is now ready for rational design. The studies described here all provide evidence for the origins of rate acceleration, derived in large part from the results of quantum chemical calculations, that can now be applied to the design of new catalysts for [3s,3s] and other sigmatropic shifts.
Co-reporter:T. E. O'Brien, S. J. Bertolani, D. J. Tantillo and J. B. Siegel
Chemical Science 2016 vol. 7(Issue 7) pp:4009-4015
Publication Date(Web):21 Mar 2016
DOI:10.1039/C6SC00635C
Sesquiterpenoids comprise a class of terpenoid natural products with thousands of compounds that are highly diverse in structure, generally containing a polycyclic carbon backbone that is constructed by a sesquiterpene synthase. Decades of experimental and computational studies have demonstrated that these enzymes generate a carbocation in the active site, which undergoes a series of structural rearrangements until a product is formed via deprotonation or nucleophile attack. However, for the vast majority of these enzymes the productive binding orientation of the intermediate carbocations has remained unclear. In this work, a method that combines quantum mechanics and computational docking is used to generate an all-atom model of every putative intermediate formed in the context of the enzyme active site for tobacco epi-aristolochene synthase (TEAS). This method identifies a single pathway that links the first intermediate to the last, enabling us to propose the first high-resolution model for the reaction intermediates in the active site of TEAS, and providing testable predictions.
Co-reporter:Dean J. Tantillo
Organic Letters 2016 Volume 18(Issue 18) pp:4482-4484
Publication Date(Web):August 25, 2016
DOI:10.1021/acs.orglett.6b01919
Heathcock’s classic cyclization/rearrangement cascade for formation of Daphniphyllum alkaloids is subjected to analysis using density functional theory calculations. The results of these calculations are consistent with a two-step pathway involving two pericyclic reactions, a Diels–Alder cycloaddition and an ene reaction.
Co-reporter:David R. Williams, J. Cullen Klein, Lucas C. Kopel, Nhu Nguyen, and Dean J. Tantillo
Organic Letters 2016 Volume 18(Issue 3) pp:424-427
Publication Date(Web):January 19, 2016
DOI:10.1021/acs.orglett.5b03464
Studies have advanced a stereocontrolled pathway for the synthesis of australifungin. Elaboration of the trans-fused IMDA product 4 led to the cis-diol 15, which produced the α-hydroxyenone 19 upon oxidation. Computational studies on model systems indicate that the keto–enol tautomer shown for 19 is higher in energy than the keto–enol tautomer represented by the natural product 1. The reactivity of 19 does not permit mild isomerization and subsequent deprotection to yield 1. These findings raise new questions regarding the synthesis and bioactivity of australifungin and related natural products.
Co-reporter:Henry B. Wedler, T. Newman, and Dean J. Tantillo
Journal of Natural Products 2016 Volume 79(Issue 10) pp:2744-2748
Publication Date(Web):September 22, 2016
DOI:10.1021/acs.jnatprod.6b00348
Density functional theory (DFT) calculations are used to probe the validity of mechanistic proposals for the conversion of isozizanoic acid to 12-norisoziza-5-ene, a reaction that occurs during steam distillation of vetiver oil. While this conversion corresponds overall to a simple decarboxylation, a multistep mechanism involving carbocation intermediates is supported by the computational results.
Co-reporter:B. M. Hudson, E. Nguyen and D. J. Tantillo
Organic & Biomolecular Chemistry 2016 vol. 14(Issue 16) pp:3975-3980
Publication Date(Web):30 Mar 2016
DOI:10.1039/C6OB00254D
Sulfur–lone pair interactions are important conformational control elements in sulfur-containing heterocycles that abound in pharmaceuticals, natural products, agrochemicals, polymers and other important classes of organic molecules. Nonetheless, the role of intramolecular sulfur–lone pair interactions in the binding of small molecules to receptors is often overlooked. Here we analyze the magnitudes and origins of these interactions for a variety of biologically relevant small molecules using quantum chemical and automated docking calculations. In most cases examined in this study, the lowest energy conformation of the small molecule displays a sulfur–lone pair close contact. However, docking studies, both published and new, often predict that conformations without sulfur–lone pair contacts have the best binding affinity for their respective receptors. This is a serious problem. Since many of these predicted bound conformations are not actually energetically accessible, pursuing design (e.g., drug design) around these binding modes necessarily will lead, serendipity aside, to dead end designs. Our results constitute a caution that one best not neglect these interactions when predicting the binding affinities of potential ligands (drugs or not) for hosts (enzymes, receptors, DNA, RNA, synthetic hosts). Moreover, a better understanding and awareness of sulfur–lone pair interactions should facilitate the rational modulation of host–guest interactions involving sulfur-containing molecules.
Co-reporter:Q Nhu N Nguyen and Dean J Tantillo
The Journal of Antibiotics 2016 69(7) pp:534-540
Publication Date(Web):May 18, 2016
DOI:10.1038/ja.2016.51
Density functional theory calculations of 1H and 13C chemical shifts are used to assign the relative configurations of isohirsut-1-ene, isohirsut-4-ene and tsukubadiene, three terpenes previously isolated from an engineered Streptomyces.
Co-reporter:Q. Nhu N. Nguyen and Dean J. Tantillo
The Journal of Organic Chemistry 2016 Volume 81(Issue 13) pp:5295-5302
Publication Date(Web):May 26, 2016
DOI:10.1021/acs.joc.6b00533
Several Brummond–Chen thermal intramolecular (2 + 2)-cycloaddition reactions were examined using density functional theory calculations. The results of these calculations indicate that it is possible for these reactions to involve diradical intermediates that form directly from zwitterionic transition state structures. The likelihood of this scenario was shown to be sensitive to both the nature of substituents and solvent polarity.
Co-reporter:Krishna Sharma; Jamie R. Wolstenhulme; Phillip P. Painter; David Yeo; Francisca Grande-Carmona; Craig P. Johnston; Dean J. Tantillo;Martin D. Smith
Journal of the American Chemical Society 2015 Volume 137(Issue 41) pp:13414-13424
Publication Date(Web):September 23, 2015
DOI:10.1021/jacs.5b08834
A catalytic enantioselective approach to the synthesis of indolines bearing two asymmetric centers, one of which is all-carbon and quaternary, is described. This reaction proceeds with high levels of diastereoselectivity (>20:1) and high levels of enantioselectivity (up to 99.5:0.5 er) in the presence of CsOH·H2O and a quinine-derived ammonium salt. The reaction most likely proceeds via a delocalized 2-aza-pentadienyl anion that cyclizes either by a suprafacial electrocyclic mechanism, or through a kinetically controlled 5-endo-trig Mannich process. Density functional theory calculations are used to probe these two mechanistic pathways and lead to the conclusion that a nonpericyclic mechanism is most probable. The base-catalyzed interconversion of diastereoisomeric indolines in the presence of certain quaternary ammonium catalysts is observed; this may be rationalized as a cycloreversion–cyclization process. Mechanistic investigations have demonstrated that the reaction is initiated via a Mąkosza-like interfacial process, and kinetic analysis has shown that the reaction possesses a significant induction period consistent with autoinduction. A zwitterionic quinine-derived entity generated by deprotonation of an ammonium salt with the anionic reaction product is identified as a key catalytic species and the role that protonation plays in the enantioselective process outlined. We also propose that the reaction subsequently occurs entirely within the organic phase. Consequently, the reaction may be better described as a phase-transfer-initiated rather than a phase-transfer-catalyzed process; this observation may have implications for mechanistic pathways followed by other phase-transfer-mediated reactions.
Co-reporter:Reed T. Larson; Ryan P. Pemberton; Jenna M. Franke; Dean J. Tantillo;Regan J. Thomson
Journal of the American Chemical Society 2015 Volume 137(Issue 34) pp:11197-11204
Publication Date(Web):August 25, 2015
DOI:10.1021/jacs.5b07710
The enantioselective total syntheses of himandravine and GB17 were completed through a common biomimetic strategy involving Diels–Alder reactions of unusual double diene containing linear precursors. The double diene precursors, containing or lacking a C12 substituent as required to produce GB17 or himandravine, respectively, were found to undergo Diels–Alder reactions to afford mixtures of regioisomeric cycloadducts that map onto the alternative carbocyclic frameworks of both himandravine and GB17. Computational investigations revealed that these Diels–Alder reactions proceed via transition state structures of similar energy that have a high degree of bispericyclic character and that the low levels of regioselectivity observed in the reactions are a consequence of competing orbital interaction and distortion energies. The combined experimental and computational results provide valuable insights into the biosynthesis of the Galbulimima alkaloids.
Co-reporter:Ryan Van Hoveln; Brandi M. Hudson; Henry B. Wedler; Desiree M. Bates; Gabriel Le Gros; Dean J. Tantillo;Jennifer M. Schomaker
Journal of the American Chemical Society 2015 Volume 137(Issue 16) pp:5346-5354
Publication Date(Web):March 31, 2015
DOI:10.1021/ja511236d
An ongoing challenge in modern catalysis is to identify and understand new modes of reactivity promoted by earth-abundant and inexpensive first-row transition metals. Herein, we report a mechanistic study of an unusual copper(I)-catalyzed 1,3-migration of 2-bromostyrenes that reincorporates the bromine activating group into the final product with concomitant borylation of the aryl halide bond. A combination of experimental and computational studies indicated this reaction does not involve any oxidation state changes at copper; rather, migration occurs through a series of formal sigmatropic shifts. Insight provided from these studies will be used to expand the utility of aryl copper species in synthesis and develop new ligands for enantioselective copper-catalyzed halogenation.
Co-reporter:Jason G. Harrison; Osvaldo Gutierrez; Navendu Jana; Tom G. Driver
Journal of the American Chemical Society 2015 Volume 138(Issue 2) pp:487-490
Publication Date(Web):December 31, 2015
DOI:10.1021/jacs.5b11427
Possible mechanisms for Rh-promoted indole formation from vinyl/azidoarenes were examined computationally, and a mechanism is proposed in which the Rh catalyst promotes generation of a nitrene but is not directly involved in cyclization.
Co-reporter:Young J. Hong; José-Luis Giner
Journal of the American Chemical Society 2015 Volume 137(Issue 5) pp:2085-2088
Publication Date(Web):January 21, 2015
DOI:10.1021/ja512901a
Theoretical investigation of cyclopropane-to-cyclopropane rearrangements of sterols indicates a role for highly delocalized bicyclobutonium ions in biosynthesis.
Co-reporter:Young J. Hong
Journal of the American Chemical Society 2015 Volume 137(Issue 12) pp:4134-4140
Publication Date(Web):March 12, 2015
DOI:10.1021/ja512685x
On the basis of results from quantum chemical calculations, the feasibility of an extensive series of intramolecular proton-transfer reactions postulated to occur during terpene biosynthesis is assessed and guiding principles are proposed.
Co-reporter:Q. Nhu N. Nguyen, Michael W. Lodewyk, Silvia Bezer, Michel R. Gagné, Marcey L. Waters, and Dean J. Tantillo
ACS Catalysis 2015 Volume 5(Issue 3) pp:1617
Publication Date(Web):January 28, 2015
DOI:10.1021/cs5019277
The impact of the macrodipole of peptide helices on catalysis was examined using density functional theory calculations. Transition state structures for histidine-containing polyalanine nucleophilic catalysts adding to carbonyls were computed, and the impact of both global and local noncovalent interactions was assessed. Although the peptide macrodipole appears to influence energy barriers, local interactions dominate.Keywords: catalysis; dipole; imidazole; peptide; α-helix; π-hole
Co-reporter:Ryan P. Pemberton, Krystina C. Ho and Dean J. Tantillo
Chemical Science 2015 vol. 6(Issue 4) pp:2347-2353
Publication Date(Web):02 Feb 2015
DOI:10.1039/C4SC03782K
The relative importance of preorganization, selective transition state stabilization and inherent reactivity are assessed through quantum chemical and docking calculations for a sesquiterpene synthase (epi-isozizaene synthase, EIZS). Inherent reactivity of the bisabolyl cation, both static and dynamic, appears to determine the pathway to product, although preorganization and selective binding of the final transition state structure in the multi-step carbocation cascade that forms epi-isozizaene appear to play important roles.
Co-reporter:Young J. Hong and Dean J. Tantillo
Organic Letters 2015 Volume 17(Issue 21) pp:5388-5391
Publication Date(Web):October 27, 2015
DOI:10.1021/acs.orglett.5b02740
Density functional theory calculations on a carbocation rearrangement relevant to the biosynthesis of the sesquiterpenoid trefolane A are described, with a focus on the viability of altering the curvature of the potential energy surface through C–H···π interactions of the sort likely to be found at the active site of a terpene synthase enzyme. These interactions are able to remove a deep minimum from a pathway to product.
Co-reporter:Teresa A. Palazzo, Digambara Patra, Joung S. Yang, Elsy El Khoury, Mackenzie G. Appleton, Makhluf J. Haddadin, Dean J. Tantillo, and Mark J. Kurth
Organic Letters 2015 Volume 17(Issue 23) pp:5732-5735
Publication Date(Web):November 17, 2015
DOI:10.1021/acs.orglett.5b02680
A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λmax of excitation for DBNs with varying electronic character.
Co-reporter:Young J. Hong and Dean J. Tantillo
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 45) pp:11140-11140
Publication Date(Web):03 Nov 2015
DOI:10.1039/C5OB90181B
Correction for ‘The energetic viability of an unexpected skeletal rearrangement in cyclooctatin biosynthesis’ by Young J. Hong and Dean J. Tantillo, Org. Biomol. Chem., 2015, 13, 10273–10278.
Co-reporter:Young J. Hong and Dean J. Tantillo
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 41) pp:10273-10278
Publication Date(Web):10 Sep 2015
DOI:10.1039/C5OB01785H
Results of density functional theory calculations on possible mechanisms for formation of the diterpenoid cyclooctatin are described. These results are consistent with the involvement of an unexpected 1,3-alkyl shift that interconverts two cyclopropylcarbinyl carbocations and interchanges the positions of two carbon atoms in an 8-membered ring. Predictions for future experiments to provide further support of this mechanism also are described.
Co-reporter:Teresa A. Palazzo; Tiana T. Truong; Shirley M. T. Wong; Emma T. Mack; Michael W. Lodewyk; Jason G. Harrison; R. Alan Gamage; Justin B. Siegel; Mark J. Kurth
Journal of Chemical Education 2015 Volume 92(Issue 3) pp:561-566
Publication Date(Web):November 14, 2014
DOI:10.1021/ed4006584
An applied computational chemistry laboratory exercise is described in which students use modern quantum chemical calculations of chemical shifts to assign the structure of a recently isolated natural product. A pre/post assessment was used to measure student learning gains and verify that students demonstrated proficiency of key learning objectives.
Co-reporter:Dr. Sebastian Strych;Dr. Guillaume Journot;Ryan P. Pemberton;Dr. Selina C. Wang;Dr. Dean J. Tantillo;Dr. Dirk Trauner
Angewandte Chemie International Edition 2015 Volume 54( Issue 17) pp:
Publication Date(Web):
DOI:10.1002/anie.201502755
Co-reporter:Dr. Sebastian Strych;Dr. Guillaume Journot;Ryan P. Pemberton;Dr. Selina C. Wang;Dr. Dean J. Tantillo;Dr. Dirk Trauner
Angewandte Chemie International Edition 2015 Volume 54( Issue 17) pp:5079-5083
Publication Date(Web):
DOI:10.1002/anie.201411350
Abstract
A biomimetic total synthesis of santalin Y, a structurally complex but racemic natural product, is described. The key step is proposed to be a (3+2) cycloaddition of a benzylstyrene to a “vinylogous oxidopyrylium”, which is followed by an intramolecular Friedel–Crafts reaction. This cascade generates the unique oxafenestrane framework of the target molecule and sets its five stereocenters in one operation. Our work provides rapid access to santalin Y and clarifies its biosynthetic relationship with other colorants isolated from red sandalwood.
Co-reporter:Dr. Sebastian Strych;Dr. Guillaume Journot;Ryan P. Pemberton;Dr. Selina C. Wang;Dr. Dean J. Tantillo;Dr. Dirk Trauner
Angewandte Chemie 2015 Volume 127( Issue 17) pp:5168-5172
Publication Date(Web):
DOI:10.1002/ange.201411350
Abstract
Eine biomimetische Totalsynthese von Santalin Y, einem strukturell komplexen, jedoch racemischen Naturstoff, wird beschrieben. Ihr Schlüsselschritt ist eine (3+2)-Cycloaddition eines Benzylstilbens an ein “vinyloges Oxidopyrylium”, gefolgt von einer intramolekularen Friedel-Crafts-Reaktion. Diese Kaskade erzeugt das einzigartige Oxafenestran-Gerüst des Zielmoleküls und setzt seine fünf Stereozentren in einem einzigen Vorgang. Unsere Arbeit liefert einen schnellen Zugang zu Santalin Y und klärt dessen biosynthetische Beziehung zu anderen aus rotem Sandelholz isolierten Farbstoffen auf.
Co-reporter:Trevor A. Hamlin, Christian S. Hamann, and Dean J. Tantillo
The Journal of Organic Chemistry 2015 Volume 80(Issue 8) pp:4046-4053
Publication Date(Web):March 30, 2015
DOI:10.1021/acs.joc.5b00381
The stabilizing features of a macrocyclic sesquiterpene-derived cation were explored using quantum mechanical calculations. The monocyclic humulyl cation, the product of 11,1-cyclization of farnesyl diphosphate, is the product of the first committed step in the enzymatic synthesis of a range of structurally diverse sesquiterpenes, including humulene (monocyclic); caryophyllene (bicyclic); and protoilludene, pentalenene, and isocomene (tricyclic). These natural products are formed via carbocation cascades that are directed in part by the conformation of the humulyl cation. Understanding the mechanistic details of product formation requires an understanding of the conformational preferences of this fundamental intermediate. Replacing the carbocation with borane (preserving π-accepting capabilities), ammonium (preserving positive charge), and methylene (preserving neither π-accepting capabilities nor charge) provides a systematic method to distinguish electrostatic and orbital effects on structure and internal stabilization. Several modes of internal stabilization—hyperconjugation, transannular π(alkene)···C+ and transannular C–H···C+ interactions—were uncovered, confirming and extending previous studies on this and similar systems.
Co-reporter:Phillip P. Painter, Matthew R. Siebert, and Dean J. Tantillo
The Journal of Organic Chemistry 2015 Volume 80(Issue 23) pp:11699-11705
Publication Date(Web):July 13, 2015
DOI:10.1021/acs.joc.5b00996
Herein we describe our exploration, using density functional theory calculations, of a conjugate addition–rearrangement sequence that leads to medium-ring cyclic amines. On the basis of the results of our calculations, we conclude that the rearrangement step is rate determining. In addition, we analyze the role of a carbanion lone pair in the rearrangement step, concluding that it functions as a substituent on a [3,3] sigmatropic shift, rather than a nucleophile; thus, the Woodward–Hoffmann rules are not circumvented in this reaction via involvement of orthogonal orbitals on an atom involved in the rearrangement.
Co-reporter:Laura S. Kocsis, Husain N. Kagalwala, Sharlene Mutto, Bhaskar Godugu, Stefan Bernhard, Dean J. Tantillo, and Kay M. Brummond
The Journal of Organic Chemistry 2015 Volume 80(Issue 23) pp:11686-11698
Publication Date(Web):February 11, 2015
DOI:10.1021/acs.joc.5b00200
The Diels–Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels–Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene–ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified conditions that can be used to achieve efficient, high-yielding, and selective IMDDA reactions of styrene–ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes makes this transformation appealing for the synthesis of medicinal and material targets. The mechanistic studies within may impact the development of other thermal transformations.
Co-reporter:Dr. Sebastian Strych;Dr. Guillaume Journot;Ryan P. Pemberton;Dr. Selina C. Wang;Dr. Dean J. Tantillo;Dr. Dirk Trauner
Angewandte Chemie 2015 Volume 127( Issue 17) pp:
Publication Date(Web):
DOI:10.1002/ange.201502755
Co-reporter:Young J. Hong and Dean J. Tantillo
Chemical Society Reviews 2014 vol. 43(Issue 14) pp:5042-5050
Publication Date(Web):07 Apr 2014
DOI:10.1039/C3CS60452G
Biosynthetic production of cyclobutanes leads to many complex natural products. Recently, theoretical work employing quantum chemical calculations has shed light on many of the details of cyclobutane-formation, in particular, for terpene natural products. Specific insights and general principles derived from these theoretical studies are described herein.
Branching Out from the Bisabolyl Cation. Unifying Mechanistic Pathways to Barbatene, Bazzanene, Chamigrene, Chamipinene, Cumacrene, Cuprenene, Dunniene, Isobazzanene, Iso-γ-bisabolene, Isochamigrene, Laurene, Microbiotene, Sesquithujene, Sesquisabinene, Thujopsene, Trichodiene, and Widdradiene Sesquiterpenes
Co-reporter:Young J. Hong
Journal of the American Chemical Society 2014 Volume 136(Issue 6) pp:2450-2463
Publication Date(Web):January 23, 2014
DOI:10.1021/ja4106489
Quantum chemical calculations on the transformation of the bisabolyl cation into an array of sesquiterpenes (iso-γ-bisabolene, trichodiene, cuprenene, laurene, isochamigrene, chamigrene, chamipinene, sesquithujene, sesquisabinene, microbiotene, dunniene, cumacrene, isobazzanene, bazzanene, barbatene, widdradiene, and thujopsene) are described. The bisabolyl cation is the hub of a complicated web of carbocations involved in the construction of diverse and complex molecular architectures present in a large number of Nature’s sesquiterpenoids. The results of quantum chemical calculations on the multitude of rearrangements described herein provide reasonable answers to several persistent mechanistic questions in the world of terpene biosynthesis and also provide examples of general reactivity principles for terpene-forming (and other) carbocation rearrangements.
Co-reporter:Ryan P. Pemberton and Dean J. Tantillo
Chemical Science 2014 vol. 5(Issue 8) pp:3301-3308
Publication Date(Web):02 Jun 2014
DOI:10.1039/C4SC00674G
The lifetimes of secondary carbocations proposed to occur along reaction coordinates for terpene-forming carbocation rearrangements were estimated from direct dynamics simulations using density functional theory. Classical secondary carbocations supported by bicyclo[2.2.1] and bicyclo[2.2.2] frameworks have distinct characteristic lifetimes, ca. 40 and 90 fs, respectively. The fusion of additional rings to these frameworks was found to have little effect on these lifetimes, despite altering the potential energy surfaces for rearrangement. Inherent dynamical tendencies of secondary carbocations are shown to be manipulable by alkylation and enforced intermolecular interactions.
Co-reporter:Miho Isegawa, Satoshi Maeda, Dean J. Tantillo and Keiji Morokuma
Chemical Science 2014 vol. 5(Issue 4) pp:1555-1560
Publication Date(Web):03 Feb 2014
DOI:10.1039/C3SC53293C
Application of the Artificial Force Induced Reaction (AFIR) method to the prediction of cyclization/rearrangement pathways for carbocation precursors to sesquiterpenes is described. This method captures many of the features revealed in previous studies as well as new ones, including a pathway to a sesquiterpene not yet isolated in nature that we suspect will be isolated in time.
Co-reporter:Christopher M. Rasik, Young J. Hong, Dean J. Tantillo, and M. Kevin Brown
Organic Letters 2014 Volume 16(Issue 19) pp:5168-5171
Publication Date(Web):September 17, 2014
DOI:10.1021/ol5025184
A detailed analysis of a Lewis acid promoted ketene–alkene [2 + 2] cycloaddition is reported. The studies have led to a rationalization for an observed inversion of diastereoselectivity between thermally induced and Lewis acid promoted ketene–alkene [2 + 2] cycloadditions. The model is supported with both experimental and computational results.
Co-reporter:Phillip P. Painter, Bonnie M. Wong, and Dean J. Tantillo
Organic Letters 2014 Volume 16(Issue 18) pp:4818-4821
Publication Date(Web):September 4, 2014
DOI:10.1021/ol5023036
The theoretical investigation of concerted and stepwise Cope rearrangements of natural products led to the prediction that some concerted Cope rearrangements can be promoted by noncovalent association of their transition state structures with ammonium cations.
Co-reporter:David R. Williams, Bruce A. Atwater, Seth A. Bawel, Pucheng Ke, Osvaldo Gutierrez, and Dean J. Tantillo
Organic Letters 2014 Volume 16(Issue 2) pp:468-471
Publication Date(Web):December 31, 2013
DOI:10.1021/ol403351x
Asymmetric SE′ reactions of (E)- and (Z)-γ-substituted-α,β-unsaturated aldehydes have been studied for the stereocontrolled preparation of nonracemic alcohols. Mild exchange reactions of allylic stannanes provide access to chiral 1,3-bis(tolylsulfonyl)-4,5-diphenyl-1,3-diaza-2-borolidines. These reagents display reactivity with the γ-substituted α,β-unsaturated aldehydes, which is characterized by matched and mismatched elements of stereocontrol. Computational analysis (using density functional theory) provides valuable insights to guide reaction development.
Co-reporter:Michael W. Lodewyk, Dan Willenbring and Dean J. Tantillo
Organic & Biomolecular Chemistry 2014 vol. 12(Issue 6) pp:887-894
Publication Date(Web):2013/11/29
DOI:10.1039/C3OB42005A
Quantum chemical calculations are used to assess various means of lowering the barrier for the dyotropic rearrangement previously proposed to occur during the carbocation rearrangement process promoted by pentalenene synthase. Several means of lowering this barrier, including a stepwise pathway for dyotropic rearrangement, are uncovered.
Co-reporter:Young J. Hong
Helvetica Chimica Acta 2014 Volume 97( Issue 11) pp:1475-1480
Publication Date(Web):
DOI:10.1002/hlca.201400082
Abstract
The results of quantum-chemical calculations aimed at assessing the viability of nonclassical carbocations proposed to be involved in the biosynthesis of atiserne, beyerene, kaurene, and trachylobane diterpenes are presented. While the proposed edge-protonated structure is much lower in energy than the proposed face-protonated structure, neither is predicted to be a viable intermediate energetically.
Co-reporter:Q. Nhu N. Nguyen, Jiong Yang, and Dean J. Tantillo
The Journal of Organic Chemistry 2014 Volume 79(Issue 15) pp:7162-7168
Publication Date(Web):July 7, 2014
DOI:10.1021/jo5013064
The reactivity of macrocyclic bis-enones in Diels–Alder reactions was examined using quantum chemical calculations. Stepwise pathways for these transannular cycloaddition reactions were shown to predominate. Steric interactions and torsional strain appeared to play a major role in controlling the overall barrier for polycycle formation.
Co-reporter:Phillip P. Painter, Ryan P. Pemberton, Bonnie M. Wong, Krystina C. Ho, and Dean J. Tantillo
The Journal of Organic Chemistry 2014 Volume 79(Issue 1) pp:432-435
Publication Date(Web):November 15, 2013
DOI:10.1021/jo402487d
Although evidence has mounted in recent years for the biosynthetic relevance of [4 + 2] cycloaddition reactions, other cycloadditions have received much less attention. Herein we used density functional theory (DFT) calculations to assess the viability of nitrone–alkene (3 + 2) cycloaddition reactions proposed to occur during the biosynthesis of several alkaloid natural products (flueggines and virosaines). The results of our calculations indicate that these reactions have low enough intrinsic barriers and diastereoselectivity that they can proceed without enzymatic intervention.
Co-reporter:Quynh Nhu N. Nguyen ; Dean J. Tantillo
Chemistry – An Asian Journal 2014 Volume 9( Issue 3) pp:674-680
Publication Date(Web):
DOI:10.1002/asia.201301452
Abstract
This account discusses representative case studies for various applications of quantum chemical calculations in synthetic organic chemistry. These include confirmation of target structures, methodology development, and catalyst design. These examples demonstrate how predictions from quantum chemical calculations can be utilized to streamline synthetic efforts.
Co-reporter:Kazumitsu Onizuka ; Jason G. Harrison ; Alexi A. Ball-Jones ; José M. Ibarra-Soza ; Yuxuan Zheng ; Diana Ly ; Walter Lam ; Stephanie Mac ; Dean J. Tantillo ;Peter A. Beal
Journal of the American Chemical Society 2013 Volume 135(Issue 45) pp:17069-17077
Publication Date(Web):October 23, 2013
DOI:10.1021/ja4079754
Short interfering RNAs (siRNAs) are promising drug candidates for a wide range of targets including those previously considered “undruggable”. However, properties associated with the native RNA structure limit drug development, and chemical modifications are necessary. Here we describe the structure-guided discovery of functional modifications for the guide strand 5′-end using computational screening with the high-resolution structure of human Ago2, the key nuclease on the RNA interference pathway. Our results indicate the guide strand 5′-end nucleotide need not engage in Watson–Crick (W/C) H-bonding but must fit the general shape of the 5′-end binding site in MID/PIWI domains of hAgo2 for efficient knockdown. 1,2,3-Triazol-4-yl bases formed from the CuAAC reaction of azides and 1-ethynylribose, which is readily incorporated into RNA via the phosphoramidite, perform well at the guide strand 5′-end. In contrast, purine derivatives with modified Hoogsteen faces or N2 substituents are poor choices for 5′-end modifications. Finally, we identified a 1,2,3-triazol-4-yl base incapable of W/C H-bonding that performs well at guide strand position 12, where base pairing to target was expected to be important. This work expands the repertoire of functional nucleotide analogues for siRNAs.
Co-reporter:Pradip Maity ; Ryan P. Pemberton ; Dean J. Tantillo ;Uttam K. Tambar
Journal of the American Chemical Society 2013 Volume 135(Issue 44) pp:16380-16383
Publication Date(Web):October 28, 2013
DOI:10.1021/ja4095473
Although the aromatic aza-Claisen rearrangement is a general strategy for accessing substituted aromatic amines, there are no highly enantioselective examples of this process. We report the first Brønsted acid catalyzed enantioselective indole aza-Claisen rearrangement for the synthesis of chiral 3-amino-2-substituted indoles. We present evidence for an arene CH–O interaction as a source of activation and stereoinduction, which is an unprecedented phenomenon in enantioselective Brønsted acid catalysis. The products of this reaction can be transformed into 3-aminooxindoles, which are prevalent in many biologically active small molecules.
Co-reporter:Yit-Heng Chooi ; Young J. Hong ; Ralph A. Cacho ; Dean J. Tantillo ;Yi Tang
Journal of the American Chemical Society 2013 Volume 135(Issue 45) pp:16805-16808
Publication Date(Web):October 25, 2013
DOI:10.1021/ja408966t
Viridicatumtoxin (1) is a tetracycline-like fungal meroterpenoid with a unique, fused spirobicyclic ring system. Puzzlingly, no dedicated terpene cyclase is found in the gene cluster identified in Penicillium aethiopicum. Cytochrome P450 enzymes VrtE and VrtK in the vrt gene cluster were shown to catalyze C5-hydroxylation and spirobicyclic ring formation, respectively. Feeding acyclic previridicatumtoxin to Saccharomyces cerevisiae expressing VrtK confirmed that VrtK is the sole enzyme required for cyclizing the geranyl moiety. Thus, VrtK is the first example of a P450 that can catalyze terpene cyclization, most likely via initial oxidation of C17 to an allylic carbocation. Quantum chemical modeling revealed a possible new tertiary carbocation intermediate E that forms after allylic carbocation formation. Intermediate E can readily undergo concerted 1,2-alkyl shift/1,3-hydride shift, either spontaneously or further aided by VrtK, followed by C7 Friedel–Crafts alkylation to afford 1. The most likely stereochemical course of the reaction was proposed on the basis of the results of our computations.
Co-reporter:Dean J. Tantillo
Natural Product Reports 2013 vol. 30(Issue 8) pp:1079-1086
Publication Date(Web):24 Jun 2013
DOI:10.1039/C3NP70028C
Covering: up to March, 2013. This article was invited following the 2012 NPR Lectureship presented to Professor Dean Tantillo at the 21st IUPAC International Conference on Physical Organic Chemistry (ICPOC 21)This Highlight describes applications of quantum chemical calculations to problems in natural products chemistry, including the elucidation of natural product structures (distinguishing between constitutional isomers, distinguishing between diastereomers, and assigning absolute configuration) and determination of reasonable mechanisms for their formation.
Co-reporter:Osvaldo Gutierrez, Benjamin F. Strick, Regan J. Thomson and Dean J. Tantillo
Chemical Science 2013 vol. 4(Issue 10) pp:3997-4003
Publication Date(Web):22 Jul 2013
DOI:10.1039/C3SC51564H
Computational analysis of the triflimide catalyzed [3,3]-sigmatropic rearrangement of N-allylhydrazones, using density functional theory calculations, is reported. Key mechanistic insight was obtained and predictions derived therefrom were confirmed experimentally through temperature dependence studies. The computational results have led to the development of electron deficient N-allylhydrazones capable of reacting under mild reaction conditions. Application of the rearrangement to form a new sp3 stereogenic center is reported for the first time.
Co-reporter:Osvaldo Gutierrez, Jason G. Harrison, Ryan J. Felix, Fernando Cortés Guzman, Michel R. Gagné and Dean J. Tantillo
Chemical Science 2013 vol. 4(Issue 10) pp:3894-3898
Publication Date(Web):22 Jul 2013
DOI:10.1039/C3SC51657A
Quantum chemical calculations are used to explore the origins of regioselectivity for proton-, Pt(II)- and Pd(II)-promoted cyclizations of 1,5-hexadienes, 5-aminoalkenes, and allylic acetimidates. The strain associated with achieving carbonium ion-like transition state geometries is shown to be a key factor in controlling 5-exo vs. 6-endo selectivity.
Co-reporter:Young J. Hong and Dean J. Tantillo
Chemical Science 2013 vol. 4(Issue 6) pp:2512-2518
Publication Date(Web):02 Apr 2013
DOI:10.1039/C3SC50571E
Density functional theory calculations on geometries and interaction energies for C–H⋯π interactions involving carbocations are described. C–H bonds involved in strong hyperconjugation are shown to be strong C–H⋯π donors and their participation in C–H⋯π interactions with specific geometries is shown to promote large modifications to the structures of carbocations. Implications for terpene biosynthesis are discussed.
Co-reporter:Dean J. Tantillo and Paul von Ragué Schleyer
Organic Letters 2013 Volume 15(Issue 7) pp:1725-1727
Publication Date(Web):March 27, 2013
DOI:10.1021/ol4005189
The C1 nonamethylcyclopentyl cation minimum undergoes complete methyl scrambling in SbF5 with a 7 kcal/mol barrier. This corresponds to the rate-limiting conformational interconversion of enantiomeric hyperconjomers via a Cs transition structure (above right). A remarkable, more rapid, second process only exchanges methyls within sets of four and five (blue and red, see above), as has been observed experimentally at low temperatures. The computed ∼2 kcal/mol barrier involves a Cs [1s,2s] sigmatropic methyl shift transition structure (above left).
Co-reporter:Keith C. Coffman, Teresa A. Palazzo, Timothy P. Hartley, James C. Fettinger, Dean J. Tantillo, and Mark J. Kurth
Organic Letters 2013 Volume 15(Issue 8) pp:2062-2065
Publication Date(Web):April 4, 2013
DOI:10.1021/ol400787y
Reductive heterocycle–heterocycle (heterocycle → heterocycle; H–H) transformations that give 4-aminoquinolines, 3-acylindoles, and quinolin-4(1H)-ones from 2-nitrophenyl substituted isoxazoles are reported. When this methodology is applied to 3,5-, 4,5-, and 3,4-bis(2-nitrophenyl)isoxazoles, chemoselective heterocyclization gives quinolin-4(1H)-ones, and 4-aminoquinolines, exclusively.
Co-reporter:Jason G. Harrison, Yvonne B. Zheng, Peter A. Beal, and Dean J. Tantillo
ACS Chemical Biology 2013 Volume 8(Issue 11) pp:2354
Publication Date(Web):September 24, 2013
DOI:10.1021/cb4006062
The use of computational modeling techniques to gain insight into nucleobase interactions has been a challenging endeavor to date. Accurate treatment requires the tackling of many challenges but also holds the promise of great rewards. The development of effective computational approaches to predict the binding affinities of nucleobases and analogues can, for example, streamline the process of developing novel nucleobase modifications, which should facilitate the development of new RNAi-based therapeutics. This brief review focuses on available computational approaches to predicting base pairing affinity in RNA-based contexts such as nucleobase–nucleobase interactions in duplexes and nucleobase–protein interactions. The challenges associated with such modeling along with potential future directions for the field are highlighted.
Co-reporter:Brandi M. Hudson, Jason G. Harrison, Dean J. Tantillo
Tetrahedron Letters 2013 Volume 54(Issue 23) pp:2952-2955
Publication Date(Web):5 June 2013
DOI:10.1016/j.tetlet.2013.03.109
The results of quantum chemical calculations on a previously proposed biosynthetic pathway for the formation of calophyline A from rhazimol, which features formally forbidden 4-electron [1,2] and [1,3] sigmatropic shifts, are discussed. The proposed pathway was not found to be energetically viable, despite a surprisingly low predicted barrier for the [1,3] shift, but an alternative route involving a series of tautomerizations and carbonyl addition reactions is shown to be more energetically feasible.
Co-reporter:Dr. Young J. Hong;Sra Irmisch;Dr. Selina C. Wang;Dr. Stefan Garms; Jonathan Gershenzon; Liansuo Zu;Dr. Tobias G. Köllner; Dean J. Tantillo
Chemistry - A European Journal 2013 Volume 19( Issue 40) pp:13590-13600
Publication Date(Web):
DOI:10.1002/chem.201301018
Abstract
Terpene synthases, as key enzymes of terpene biosynthesis, have garnered the attention of chemists and biologists for many years. Their carbocationic reaction mechanisms are responsible for the huge variety of terpene structures in nature. These mechanisms are amenable to study by using classical biochemical approaches as well as computational analysis, and in this study we combine quantum-chemical calculations and deuterium-labeling experiments to elucidate the reaction mechanism of a triquinane forming sesquiterpene synthase from chamomile. Our results suggest that the reaction from farnesyl diphosphate to triquinanes proceeds through caryophyllyl and presilphiperfolanyl cations and involves the protonation of a stable (−)-(E)-β-caryophyllene intermediate. A tyrosine residue was identified that appears to be involved in the proton-transfer process.
Co-reporter:Rebecca L. Davis, Michael W. Lodewyk, Matthew R. Siebert, Dean J. Tantillo
Journal of Organometallic Chemistry 2013 748() pp: 68-74
Publication Date(Web):
DOI:10.1016/j.jorganchem.2013.02.034
Co-reporter:Ryan J. Felix, Osvaldo Gutierrez, Dean J. Tantillo, and Michel R. Gagné
The Journal of Organic Chemistry 2013 Volume 78(Issue 11) pp:5685-5690
Publication Date(Web):April 17, 2013
DOI:10.1021/jo400139g
Gold(I) catalysts effectively promote the Cope rearrangement of acyclic 1,5-dienes bearing a terminal cyclopropylidene. When this methodology is applied to cyclic substrates an unexpected transformation occurs, resulting in the formation of a tricyclic compound incorporating a bicyclo[4.2.0]oct-1-ene core, a portion of which is found in a number of natural products. Density functional theory calculations (M06 and M06-2X) reveal insight into the mechanism and thermodynamics of this unique transformation.
Co-reporter:Young J. Hong, José-Luis Giner, and Dean J. Tantillo
The Journal of Organic Chemistry 2013 Volume 78(Issue 3) pp:935-941
Publication Date(Web):December 27, 2012
DOI:10.1021/jo3024208
Quantum chemical calculations (B3LYP and MP2) are described for the formation and rearrangements of carbocations derived from the biological methylation reaction that produces 24-propyl sterols in pelagophyte algae. Previous mechanistic proposals are discussed in light of the results of these calculations. Of particular note is the prediction of a new triple-shift rearrangement that is inherently preferred for the biosynthetically relevant carbocations. Our calculations also reveal how these reactions may be affected by intermolecular interactions with S-adenosylmethionine.
Co-reporter:Yasuyuki Ogawa, Phillip P. Painter, Dean J. Tantillo, and Paul A. Wender
The Journal of Organic Chemistry 2013 Volume 78(Issue 1) pp:104-115
Publication Date(Web):November 2, 2012
DOI:10.1021/jo301953h
The Prins cyclization of syn-β-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidenetetrahydropyrans as sole products in excellent yields regardless of the aldehyde (R″) or syn-β-hydroxy allylsilane substituent (R′) used. By reversing the R″ and R′ groups, complementary exocyclic stereocontrol can be achieved. When the anti-β-hydroxy allylsilanes are used, the Prins cyclization gives predominantly cis-2,6-disubstituted 4-alkylidenetetrahydropyrans, now with the opposite olefin geometry in excellent yield. The proposed reaction mechanism and the observed stereoselectivity for these processes are supported by DFT calculations.
Co-reporter:Michael W. Lodewyk ; Cristian Soldi ; Paul B. Jones ; Marilyn M. Olmstead ; Juan Rita ; Jared T. Shaw
Journal of the American Chemical Society 2012 Volume 134(Issue 45) pp:18550-18553
Publication Date(Web):October 29, 2012
DOI:10.1021/ja3089394
Aquatolide has been reisolated from its natural source, and its structure has been revised on the basis of quantum-chemical NMR calculations, extensive experimental NMR analysis, and crystallography.
Co-reporter:Liansuo Zu ; Meimei Xu ; Michael W. Lodewyk ; David E. Cane ; Reuben J. Peters
Journal of the American Chemical Society 2012 Volume 134(Issue 28) pp:11369-11371
Publication Date(Web):June 27, 2012
DOI:10.1021/ja3043245
Mechanistic proposals for the carbocation cascade reaction leading to the tricyclic sesquiterpene pentalenene are assessed in light of the results of isotopically sensitive branching experiments with the H309A mutant of pentalenene synthase. These experimental results support a mechanism for pentalenene formation involving a 7-protoilludyl cation whose intermediacy was first predicted using quantum-chemical calculations.
Co-reporter:Jason G. Harrison and Dean J. Tantillo
Physical Chemistry Chemical Physics 2012 vol. 14(Issue 43) pp:14756-14759
Publication Date(Web):02 Jul 2012
DOI:10.1039/C2CP41844D
Density functional theory calculations are used to predict structures and reactivity (barriers for sigmatropic shifts and retrocycloadditions) of 1,5-hexadienes fused to cubanes.
Co-reporter:Vicky Sio, Jason G. Harrison, Dean J. Tantillo
Tetrahedron Letters 2012 Volume 53(Issue 51) pp:6919-6922
Publication Date(Web):19 December 2012
DOI:10.1016/j.tetlet.2012.10.019
Results from density functional theory calculations on a proton-promoted [2+2] cycloaddition to form plumisclerin A’s cyclobutane ring are described. On the basis of these results, it is proposed that protonation allows for an energetically viable stepwise cycloaddition that provides an alternative to photochemical cyclobutane formation.
Co-reporter:Henry B. Wedler, Sarah R. Cohen, Rebecca L. Davis, Jason G. Harrison, Matthew R. Siebert, Dan Willenbring, Christian S. Hamann, Jared T. Shaw, and Dean J. Tantillo
Journal of Chemical Education 2012 Volume 89(Issue 11) pp:1400-1404
Publication Date(Web):September 7, 2012
DOI:10.1021/ed3000364
We describe accommodations that we have made to our applied computational–theoretical chemistry laboratory to provide access for blind and visually impaired students interested in independent investigation of structure–function relationships. Our approach utilizes tactile drawings, molecular model kits, existing software, Bash and Perl scripts written in-house, and three-dimensional printing in a process that allows a blind or visually impaired student to satisfy her or his curiosity about structure–function relationships with minimal assistance from sighted co-workers.Keywords: Computational Chemistry; Computer-Based Learning; Graduate Education/Research; Inquiry-Based/Discovery Learning; Laboratory Computing/Interfacing; Molecular Properties/Structure; Organic Chemistry; Quantum Chemistry; Theoretical Chemistry; Undergraduate Research;
Co-reporter:Young J. Hong, Robert Ponec, and Dean J. Tantillo
The Journal of Physical Chemistry A 2012 Volume 116(Issue 35) pp:8902-8909
Publication Date(Web):August 11, 2012
DOI:10.1021/jp3047328
The nature of the recently described “triple shift” rearrangement of a biologically relevant carbocation (computed in the absence of a surrounding enzyme) is characterized by examining the evolution of charge distribution, molecular volume, accessible surface area, and multicenter bonding indices along its reaction coordinate. Implications for interaction of the rearranging carbocation with a terpene synthase active site are discussed.
Co-reporter:Osvaldo Gutierrez;Jason G. Harrison;Ryan P. Pemberton ; Dean J. Tantillo
Chemistry - A European Journal 2012 Volume 18( Issue 35) pp:11029-11035
Publication Date(Web):
DOI:10.1002/chem.201201193
Abstract
DFT (both B3LYP and M06-2X), CASSCF, and CASPT2 calculations were used to investigate competing [3, 3] and [3, 5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7-octatriene. In accord with previous results on 1,5-hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3, 3] rearrangement. For the competing [3, 5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06-2X calculations predicted a different potential energy landscape: no stepwise [3, 3] pathway, only two competing [3, 5] sigmatropic shifts, and an intramolecular Diels–Alder cycloaddition/homolytic ring-opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7-octatrienes with substituents at the 4- and 7-positions.
Co-reporter:Osvaldo Gutierrez and Dean J. Tantillo
The Journal of Organic Chemistry 2012 Volume 77(Issue 20) pp:8845-8850
Publication Date(Web):September 24, 2012
DOI:10.1021/jo301864h
A survey of computational studies on the mechanisms of dyotropic, Schmidt, and related reactions is presented. Connections between synthetically applied versions of these processes and those predicted to occur during biosynthetic terpene-forming carbocation cascades are highlighted.
Co-reporter:TatyanaN. Gribanova Dr.;AndreyG. Starikov Dr.;RuslanM. Minyaev Dr.;VladimirI. Minkin Dr.;MatthewR. Siebert;DeanJ. Tantillo Dr.
Chemistry - A European Journal 2010 Volume 16( Issue 7) pp:2272-2281
Publication Date(Web):
DOI:10.1002/chem.200902004
Abstract
A series of sandwich compounds of transition metals (M=Ni, Fe, Cr) with cyclic hydrocarbon (M(CH)n) and borane (M(BH2)n), ligands (including mixed hydrocarbon/borane sandwiches) has been studied using density functional theory (B3LYP/6-311+G(df,p)). Multicenter bonding between the central metal atom and basal cycloborane rings provides stabilization to planar cycloborane species. Large negative NICS values allude to aromatic character in the cycloboranes similar to the analogous cyclic hydrocarbons. The ability of cycloborane sandwiches to stabilize attached carbocations, radicals and carbanions is also assessed.
Co-reporter:Liping Meng;Selina C. Wang;James C. Fettinger;Mark J. Kurth
European Journal of Organic Chemistry 2009 Volume 2009( Issue 10) pp:1578-1584
Publication Date(Web):
DOI:10.1002/ejoc.200801211
Abstract
Herein we describe a combined experimental/theoretical study on the effects of substituents on regio- and stereoselectivity in intramolecular 1,3-dipolar cycloadditions of nitrones and alkenes tethered by benzimidazoles. By employing a large substituent at position R2 or R3, complete selectivity was achieved for either the fused or bridged cycloadduct, respectively. In addition, these cycloadducts were formed as single diastereomers in all of the cycloadditions examined. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Co-reporter:AndrewP. Marcus;AmyS. Lee;RebeccaL. Davis;DeanJ. Tantillo ;Richmond Sarpong
Angewandte Chemie International Edition 2008 Volume 47( Issue 34) pp:6379-6383
Publication Date(Web):
DOI:10.1002/anie.200801542
Co-reporter:AndrewP. Marcus;AmyS. Lee;RebeccaL. Davis;DeanJ. Tantillo ;Richmond Sarpong
Angewandte Chemie 2008 Volume 120( Issue 34) pp:6479-6483
Publication Date(Web):
DOI:10.1002/ange.200801542
Co-reporter:Mikail E. Abbasov, Brandi M. Hudson, Weixu Kong, Dean J. Tantillo and Daniel Romo
Organic & Biomolecular Chemistry 2017 - vol. 15(Issue 15) pp:NaN3183-3183
Publication Date(Web):2017/03/15
DOI:10.1039/C6OB02738E
α,β-Unsaturated acylammonium salts are useful dienophiles enabling highly enantioselective and stereodivergent Diels-Alder-initiated organocascades with furan-based dienes. Complex polycyclic systems can thus be obtained from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe the use of furan-based dienes bearing pendant sulfonamides leading to the generation of oxa-bridged, trans-fused tricyclic γ-lactams. This process constitutes the first highly enantio- and diastereoselective, organocatalytic Diels-Alder cycloadditions with these typically problematic dienes due to their reversibility. Computational studies suggest that the high diastereoselectivity with these furan dienes may be due to a reversible Diels-Alder cycloaddition for the endo adducts. In addition, the utility of this methodology is demonstrated through a concise approach to a core structure with similarity to the natural product isatisine A and a nonpeptidyl ghrelin-receptor inverse agonist.
Co-reporter:T. E. O'Brien, S. J. Bertolani, D. J. Tantillo and J. B. Siegel
Chemical Science (2010-Present) 2016 - vol. 7(Issue 7) pp:NaN4015-4015
Publication Date(Web):2016/03/21
DOI:10.1039/C6SC00635C
Sesquiterpenoids comprise a class of terpenoid natural products with thousands of compounds that are highly diverse in structure, generally containing a polycyclic carbon backbone that is constructed by a sesquiterpene synthase. Decades of experimental and computational studies have demonstrated that these enzymes generate a carbocation in the active site, which undergoes a series of structural rearrangements until a product is formed via deprotonation or nucleophile attack. However, for the vast majority of these enzymes the productive binding orientation of the intermediate carbocations has remained unclear. In this work, a method that combines quantum mechanics and computational docking is used to generate an all-atom model of every putative intermediate formed in the context of the enzyme active site for tobacco epi-aristolochene synthase (TEAS). This method identifies a single pathway that links the first intermediate to the last, enabling us to propose the first high-resolution model for the reaction intermediates in the active site of TEAS, and providing testable predictions.
Co-reporter:Ryan P. Pemberton, Krystina C. Ho and Dean J. Tantillo
Chemical Science (2010-Present) 2015 - vol. 6(Issue 4) pp:NaN2353-2353
Publication Date(Web):2015/02/02
DOI:10.1039/C4SC03782K
The relative importance of preorganization, selective transition state stabilization and inherent reactivity are assessed through quantum chemical and docking calculations for a sesquiterpene synthase (epi-isozizaene synthase, EIZS). Inherent reactivity of the bisabolyl cation, both static and dynamic, appears to determine the pathway to product, although preorganization and selective binding of the final transition state structure in the multi-step carbocation cascade that forms epi-isozizaene appear to play important roles.
Co-reporter:Ryan P. Pemberton and Dean J. Tantillo
Chemical Science (2010-Present) 2014 - vol. 5(Issue 8) pp:NaN3308-3308
Publication Date(Web):2014/06/02
DOI:10.1039/C4SC00674G
The lifetimes of secondary carbocations proposed to occur along reaction coordinates for terpene-forming carbocation rearrangements were estimated from direct dynamics simulations using density functional theory. Classical secondary carbocations supported by bicyclo[2.2.1] and bicyclo[2.2.2] frameworks have distinct characteristic lifetimes, ca. 40 and 90 fs, respectively. The fusion of additional rings to these frameworks was found to have little effect on these lifetimes, despite altering the potential energy surfaces for rearrangement. Inherent dynamical tendencies of secondary carbocations are shown to be manipulable by alkylation and enforced intermolecular interactions.
Co-reporter:Osvaldo Gutierrez, Jason G. Harrison, Ryan J. Felix, Fernando Cortés Guzman, Michel R. Gagné and Dean J. Tantillo
Chemical Science (2010-Present) 2013 - vol. 4(Issue 10) pp:NaN3898-3898
Publication Date(Web):2013/07/22
DOI:10.1039/C3SC51657A
Quantum chemical calculations are used to explore the origins of regioselectivity for proton-, Pt(II)- and Pd(II)-promoted cyclizations of 1,5-hexadienes, 5-aminoalkenes, and allylic acetimidates. The strain associated with achieving carbonium ion-like transition state geometries is shown to be a key factor in controlling 5-exo vs. 6-endo selectivity.
Co-reporter:Osvaldo Gutierrez, Benjamin F. Strick, Regan J. Thomson and Dean J. Tantillo
Chemical Science (2010-Present) 2013 - vol. 4(Issue 10) pp:NaN4003-4003
Publication Date(Web):2013/07/22
DOI:10.1039/C3SC51564H
Computational analysis of the triflimide catalyzed [3,3]-sigmatropic rearrangement of N-allylhydrazones, using density functional theory calculations, is reported. Key mechanistic insight was obtained and predictions derived therefrom were confirmed experimentally through temperature dependence studies. The computational results have led to the development of electron deficient N-allylhydrazones capable of reacting under mild reaction conditions. Application of the rearrangement to form a new sp3 stereogenic center is reported for the first time.
Co-reporter:B. M. Hudson, E. Nguyen and D. J. Tantillo
Organic & Biomolecular Chemistry 2016 - vol. 14(Issue 16) pp:NaN3980-3980
Publication Date(Web):2016/03/30
DOI:10.1039/C6OB00254D
Sulfur–lone pair interactions are important conformational control elements in sulfur-containing heterocycles that abound in pharmaceuticals, natural products, agrochemicals, polymers and other important classes of organic molecules. Nonetheless, the role of intramolecular sulfur–lone pair interactions in the binding of small molecules to receptors is often overlooked. Here we analyze the magnitudes and origins of these interactions for a variety of biologically relevant small molecules using quantum chemical and automated docking calculations. In most cases examined in this study, the lowest energy conformation of the small molecule displays a sulfur–lone pair close contact. However, docking studies, both published and new, often predict that conformations without sulfur–lone pair contacts have the best binding affinity for their respective receptors. This is a serious problem. Since many of these predicted bound conformations are not actually energetically accessible, pursuing design (e.g., drug design) around these binding modes necessarily will lead, serendipity aside, to dead end designs. Our results constitute a caution that one best not neglect these interactions when predicting the binding affinities of potential ligands (drugs or not) for hosts (enzymes, receptors, DNA, RNA, synthetic hosts). Moreover, a better understanding and awareness of sulfur–lone pair interactions should facilitate the rational modulation of host–guest interactions involving sulfur-containing molecules.
Co-reporter:Michael W. Lodewyk, Dan Willenbring and Dean J. Tantillo
Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 6) pp:NaN894-894
Publication Date(Web):2013/11/29
DOI:10.1039/C3OB42005A
Quantum chemical calculations are used to assess various means of lowering the barrier for the dyotropic rearrangement previously proposed to occur during the carbocation rearrangement process promoted by pentalenene synthase. Several means of lowering this barrier, including a stepwise pathway for dyotropic rearrangement, are uncovered.
Co-reporter:Jason G. Harrison and Dean J. Tantillo
Physical Chemistry Chemical Physics 2012 - vol. 14(Issue 43) pp:NaN14759-14759
Publication Date(Web):2012/07/02
DOI:10.1039/C2CP41844D
Density functional theory calculations are used to predict structures and reactivity (barriers for sigmatropic shifts and retrocycloadditions) of 1,5-hexadienes fused to cubanes.
Co-reporter:Young J. Hong and Dean J. Tantillo
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 45) pp:NaN11140-11140
Publication Date(Web):2015/11/03
DOI:10.1039/C5OB90181B
Correction for ‘The energetic viability of an unexpected skeletal rearrangement in cyclooctatin biosynthesis’ by Young J. Hong and Dean J. Tantillo, Org. Biomol. Chem., 2015, 13, 10273–10278.
Co-reporter:Young J. Hong and Dean J. Tantillo
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 41) pp:NaN10278-10278
Publication Date(Web):2015/09/10
DOI:10.1039/C5OB01785H
Results of density functional theory calculations on possible mechanisms for formation of the diterpenoid cyclooctatin are described. These results are consistent with the involvement of an unexpected 1,3-alkyl shift that interconverts two cyclopropylcarbinyl carbocations and interchanges the positions of two carbon atoms in an 8-membered ring. Predictions for future experiments to provide further support of this mechanism also are described.
Co-reporter:Young J. Hong and Dean J. Tantillo
Chemical Society Reviews 2014 - vol. 43(Issue 14) pp:NaN5050-5050
Publication Date(Web):2014/04/07
DOI:10.1039/C3CS60452G
Biosynthetic production of cyclobutanes leads to many complex natural products. Recently, theoretical work employing quantum chemical calculations has shed light on many of the details of cyclobutane-formation, in particular, for terpene natural products. Specific insights and general principles derived from these theoretical studies are described herein.
Co-reporter:Miho Isegawa, Satoshi Maeda, Dean J. Tantillo and Keiji Morokuma
Chemical Science (2010-Present) 2014 - vol. 5(Issue 4) pp:NaN1560-1560
Publication Date(Web):2014/02/03
DOI:10.1039/C3SC53293C
Application of the Artificial Force Induced Reaction (AFIR) method to the prediction of cyclization/rearrangement pathways for carbocation precursors to sesquiterpenes is described. This method captures many of the features revealed in previous studies as well as new ones, including a pathway to a sesquiterpene not yet isolated in nature that we suspect will be isolated in time.
Co-reporter:Young J. Hong and Dean J. Tantillo
Chemical Science (2010-Present) 2013 - vol. 4(Issue 6) pp:NaN2518-2518
Publication Date(Web):2013/04/02
DOI:10.1039/C3SC50571E
Density functional theory calculations on geometries and interaction energies for C–H⋯π interactions involving carbocations are described. C–H bonds involved in strong hyperconjugation are shown to be strong C–H⋯π donors and their participation in C–H⋯π interactions with specific geometries is shown to promote large modifications to the structures of carbocations. Implications for terpene biosynthesis are discussed.
Co-reporter:Stephanie R. Hare and Dean J. Tantillo
Chemical Science (2010-Present) 2017 - vol. 8(Issue 2) pp:NaN1449-1449
Publication Date(Web):2016/10/21
DOI:10.1039/C6SC03745C
Byproducts of chemical reactions are generally thought to result from the competition between two reaction pathways, each with its own rate-determining transition state structure. We show here, however, that pathways with a single transition state structure followed by a post-transition state bifurcation may also be a source of undesired products, especially those whose appearance is unexpected. The viability of this scenario for intramolecular C–H insertion reactions affording β-lactones via Rh-carbenoid intermediates is assessed through quantum chemical calculations on potential energy surfaces and quasi-classical molecular dynamics simulations. It appears that, in these cases, the rhodium catalyst is to blame for the accessibility of a second, unintended, pathway following the transition state structure for β-lactone formation that leads to fragmentation to a ketene and carbonyl compound. If an unexpected product is formed via a post-transition state bifurcation, conventional strategies for suppressing its formation are unlikely to succeed. Guidelines for recognizing the presence of a post-transition state bifurcation are described here, along with hints at means for controlling product distributions.
Co-reporter:Mikail E. Abbasov, Brandi M. Hudson, Dean J. Tantillo and Daniel Romo
Chemical Science (2010-Present) 2017 - vol. 8(Issue 2) pp:NaN1524-1524
Publication Date(Web):2016/10/25
DOI:10.1039/C6SC04273B
Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels–Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Brønsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol–Brønsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects.
Co-reporter:Selina C. Wang and Dean J. Tantillo
Organic & Biomolecular Chemistry 2017 - vol. 15(Issue 9) pp:NaN1979-1979
Publication Date(Web):2016/11/21
DOI:10.1039/C6OB02300B
The results of density functional theory calculations on thiyl radical-promoted polycyclization to form dodecahedrane are described. On the basis of these results, the proposed polycyclization is predicted to be both highly exergonic and fast. These results showcase the potential power of radical polycyclization reactions in constructing complex molecular architectures.
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![1-methyl-1H-Imidazo[4,5-c]pyridine](http://img.cochemist.com/ccimg/5100/5028-32-0.png)
![1-methyl-1H-Imidazo[4,5-c]pyridine](http://img.cochemist.com/ccimg/5100/5028-32-0_b.png)
![endo-Bicyclo[2.2.1]hept-5-ene-2-carbonitrile](http://img.cochemist.com/ccimg/2900/2888-90-6.png)
![endo-Bicyclo[2.2.1]hept-5-ene-2-carbonitrile](http://img.cochemist.com/ccimg/2900/2888-90-6_b.png)
![5H-Cyclopenta[d]pyridazine, 6,7-dihydro-1,4-diphenyl-](http://img.cochemist.com/ccimg/2300/2272-61-9.png)
![5H-Cyclopenta[d]pyridazine, 6,7-dihydro-1,4-diphenyl-](http://img.cochemist.com/ccimg/2300/2272-61-9_b.png)
![6-Nitrobicyclo[2.2.1]hept-2-ene](http://img.cochemist.com/ccimg/900/874-44-2.png)
![6-Nitrobicyclo[2.2.1]hept-2-ene](http://img.cochemist.com/ccimg/900/874-44-2_b.png)
![Tricyclo[2.2.1.0(2,6)]heptane, 1,7-dimethyl-7-(4-methyl-3-pentenyl)-, (-)-](http://img.cochemist.com/ccimg/600/512-61-8.png)
![Tricyclo[2.2.1.0(2,6)]heptane, 1,7-dimethyl-7-(4-methyl-3-pentenyl)-, (-)-](http://img.cochemist.com/ccimg/600/512-61-8_b.png)
![pyrimido[5,4-e][1,2,4]triazine](http://img.cochemist.com/ccimg/300/254-99-9.png)
![pyrimido[5,4-e][1,2,4]triazine](http://img.cochemist.com/ccimg/300/254-99-9_b.png)
![Pyrido[3,2-d]pyrimidine(7CI,8CI,9CI)](http://img.cochemist.com/ccimg/300/254-80-8.png)
![Pyrido[3,2-d]pyrimidine(7CI,8CI,9CI)](http://img.cochemist.com/ccimg/300/254-80-8_b.png)
![Pyrido[2,3-d]pyrimidine](http://img.cochemist.com/ccimg/300/254-61-5.png)
![Pyrido[2,3-d]pyrimidine](http://img.cochemist.com/ccimg/300/254-61-5_b.png)
![Pyrido[3,4-d]pyrimidine](http://img.cochemist.com/ccimg/300/253-86-1.png)
![Pyrido[3,4-d]pyrimidine](http://img.cochemist.com/ccimg/300/253-86-1_b.png)
![Diphosphoric acid,P-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-yl] ester](http://img.cochemist.com/ccimg/6700/6699-20-3.png)
![Diphosphoric acid,P-[(2E,6E,10E)-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-yl] ester](http://img.cochemist.com/ccimg/6700/6699-20-3_b.png)
![Tricyclo[2.2.1.02,6]heptane,1,7,7-trimethyl-](http://img.cochemist.com/ccimg/600/508-32-7.png)
![Tricyclo[2.2.1.02,6]heptane,1,7,7-trimethyl-](http://img.cochemist.com/ccimg/600/508-32-7_b.png)
