Bent Bond/Antiperiplanar Hypothesis and the Chemical Reactivity of Annulenes.

The properties and stereochemical reactivity of cyclobutadiene, benzene, cyclooctatetraene, and the [10]- to [14]annulenes can be uniformly rationalized through the bent bond/antiperiplanar hypothesis (BBAH). This new orbital model considers electronic delocalization between pyramidal diradical resonance structures and associated bent bonds, as it applies to aromatic, nonaromatic, and antiaromatic molecules.

Bent Bond/Antiperiplanar Hypothesis: Modulating the Reactivity and the Selectivity in the Glycosylation of Bicyclic Pyranoside Models.

Glycosylation reactions were performed on a series of bicyclic C-substituted pyranoside models to isolate and analyze factors that control the glycosylation stereoselectivities observed in carbohydrates. The bent bond/antiperiplanar hypothesis (BBAH) orbital model rationalizes all of these results by considering hyperconjugation interactions between groups at C and the two τ bonds (bent bonds) of oxocarbenium ion intermediates formed under the glycosylation conditions. According to the BBAH, nucleophiles add to oxocarbenium intermediates by S2-like antiperiplanar displacement of the weaker of their two τ bonds.

Applying the Bent Bond/Antiperiplanar Hypothesis to the Stereoselective Glycosylation of Bicyclic Furanosides.

The glycosylation stereoselectivities for a series of bicyclic furanoside models have been carried out in the presence of weak nucleophiles. These results were analyzed through the bent bond/antiperiplanar hypothesis (BBAH) orbital model to test its validity. According to the BBAH, incoming nucleophiles displace one of the two bent bonds of bicyclic oxocarbenium ion intermediates in an antiperiplanar fashion.

Thermal rearrangement of optically active tetradeuterated 2-methoxymethyl-methylenecyclopropane and the bent bond/antiperiplanar hypothesis.

The thermolysis of an optically active tetradeuterated 2-methoxymethyl methylenecyclopropane produces a specific ratio of eight possible rearrangement stereoisomers. Despite numerous efforts, this reaction and other similar transformations have defied mechanistic interpretation until now. The direct application of the bent bond/antiperiplanar hypothesis (BBAH) to this reaction produces a mechanistic model that rationalizes all the observed reaction kinetics and products.

Bent Bonds and the Antiperiplanar Hypothesis. A Model To Account for Sigmatropic [1, n]-Hydrogen Shifts.

The bent bond/antiperiplanar hypothesis (BBAH) is used to propose a mechanism-based orbital model for the facial selectivity of sigmatropic hydrogen shifts under both thermal and photochemical conditions. The BBAH analysis of these concerted rearrangements invokes transient vibrationally excited singlet diradicals in both 4 n and 4 n+2 polyenes.

Bent Bonds (τ) and the Antiperiplanar Hypothesis-The Chemistry of Cyclooctatetraene and Other CH Isomers.

The bent bond/antiperiplanar hypothesis (BBAH) has been applied to the thermal rearrangements of cyclooctatetraene and related CH isomers. This novel orbital model shows that pyramidal singlet diradical intermediates produced from thermal vibrational states of CH isomers account for their chemical reactivity.

High-Temperature Isomerization of Benzenoid Polycyclic Aromatic Hydrocarbons. Analysis through the Bent Bond and Antiperiplanar Hypothesis Orbital Model.

L. T. Scott has discovered the 1,2-swapping of carbon and hydrogen atoms which is known to take place on benzenoid aromatics (up to ∼1000 °C range).

Bent bonds (τ) and the antiperiplanar hypothesis, and the reactivity at the anomeric center in pyranosides.

The stereoselectivity of nucleophilic addition on oxocarbenium ions derived from the bicyclic pyranoside model with or without a C-OR group can be understood through the use of the bent-bond and the antiperiplanar hypothesis in conjunction with the concept of hyperconjugation as an alternative interpretive model of structure and reactivity.

Bent bonds and the antiperiplanar hypothesis - a simple model to rationalize [1,3]-sigmatropic alkyl shifts.

The bent bond/antiperiplanar (BBA) hypothesis has been applied to the analysis of [1,3]-sigmatropic alkyl shifts. These thermal rearrangements, for which there is evidence that they proceed through diradical intermediates, can be interpreted by considering their transient allyl radical structures. For the thermolysis of cyclic molecules, the preferred generation of pyramidal allyl radicals in staggered conformations is postulated on the basis of the BBA hypothesis.

Anionic polycyclization entry to tricycles related to quassinoids and terpenoids: a stereocontrolled total synthesis of (+)-cassaine.

A full account of our anionic polycyclization approach to access highly functionalized tricycles related to quassinoids and terpenoids from several optically active bicyclic enone systems and Nazarov reagents is presented. (+)-Carvone is the only chiral source used to fix the entire stereochemistry of all of the tricycles, and the stereochemical outcome of this process was unambiguously determined by X-ray crystallographic analysis. The utility of this strategy was demonstrated by the stereocontrolled construction of advanced tricycles related to the highly potent anticancer natural product bruceantin, a member of quassinoid family, and the total synthesis of the cardioactive terpenoid (+)-cassaine, a nonsteroidal inhibitor of Na(+)-K(+)-ATPase.

Synthesis of the antiproliferative agent hippuristanol and its analogues from hydrocortisone via Hg(II)-catalyzed spiroketalization: structure-activity relationship.

An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule 1 encompassed changing the functional groups on rings A and E.

Total synthesis of (+)-cassaine utilizing an anionic polycyclization strategy.

A stereoselective total synthesis of (+)-cassaine (1) via an anionic polycyclization methodology is described. Commercially available (+)-carvone (5), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polycyclization of a new substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one (4) with known 1-phenylysulfinyl-3-penten-2-one (3) provided the versatile tricycle (2) with requisite stereochemistry.

Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia.

Background: Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings.

Bent bonds, the antiperiplanar hypothesis and the theory of resonance. A simple model to understand reactivity in organic chemistry.

By taking into consideration bent bonds (τ-bonds, tau-bonds), the antiperiplanar hypothesis, the classic theory of resonance, and the preference for staggered bonds over eclipsed bonds in tetrahedral systems, a simple qualitative model is presented to rationalize the conformation and reactivity for a wide range of compounds containing double bonds and/or carbonyl groups. Alkenes, carbonyl and carboxyl derivatives, conjugated systems as well as other functional groups are revisited. This also leads to a simple model to understand aromaticity, and electrocyclic reactions.

A highly efficient access to spiroketals, mono-unsaturated spiroketals, and furans: Hg(II)-catalyzed cyclization of alkyne diols and triols.

Hg(II) salts are identified as highly efficient catalysts for the versatile construction of spiroketals from alkyne diols in aqueous conditions. Monounsaturated spiroketals and furans were accessed with equal ease when propargylic triols (or propargylic diols) were subjected to similar conditions. Even the semiprotected alkyne diols gave the corresponding spiroketals with the same ease in a cascade manner.

Synthesis of the antiproliferative agent hippuristanol and its analogues via Suárez cyclizations and Hg(II)-catalyzed spiroketalizations.

A full account of the synthesis of hippuristanol and its analogues is described. Hecogenin acetate was identified as a suitable and economical starting material for this work, and substrate-controlled stereoselection was obtained throughout the construction of the key spiroketal unit. Suárez cyclization was first used, but Hg(II)-catalyzed spiroketalization of the 3-alkyne-1,7-diol motif was finally identified as the most convenient strategy.

Efficient synthetic approach to potent antiproliferative agent hippuristanol via Hg(II)-catalyzed spiroketalization.

The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of a spiroketal unit via Hg(OTf)(2)-catalyzed oxidation/spiroketalization of the 3-alkyn-1,7-diol motif.

Versatile strategy to access tricycles related to quassinoids and triterpenes.

The reactivity of two new bicyclic cyclohexenones (13 and 27) with several Nazarov reagents is presented. A flexible synthetic strategy is developed and provides access to highly substituted tricycles related to quassinoids and triterpenes.

Total synthesis of ouabagenin and ouabain.

A full account of the total synthesis of ouabagenin and ouabain is described. A highly stereocontrolled anionic cycloaddition for the rapid construction of the basic steroid skeleton is a pivotal conversion for the whole strategy. A careful study was needed to establish the order and the sequence of functional group manipulations.

Study of very reactive tautomeric phenol dienones as dienes in Diels-Alder reactions.

Masked ortho-benzoquinones are very reactive as diene partners in Diels-Alder reactions. Careful exploration of the orbital factors that govern their surprising behavior shows that their LUMO is almost as electron demanding as that of o-benzoquinone itself. Methyl substituents at either end of their diene system influence the activation energy through modification of the reaction pathway being more or less asynchronous.

Total synthesis of (+)-cassaine via transannular Diels-Alder reaction.

A full account of the total synthesis of (+)-cassaine ( 1) using the transannular Diels-Alder (TADA) reaction as the pivotal construction is described. The strategy began from Evans' oxazolidine 8, the only chiral source used for the total stereochemical outcome of the target molecule. The key intermediate 3 was obtained from 8 in 10 steps in 40% overall yield.

Efficient parallel synthesis of macrocyclic peptidomimetics.

A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.

Synthetic approach toward the total synthesis of kempane diterpenes via transannular Diels-Alder strategy.

Total syntheses of two new (+/-)-kempane derivatives 30 and 47 were achieved with transannular Diels-Alder reaction (TADA) serving as the key step for the stereoselective formation of tricyclic [6.6.5] system 3.

Synthetic studies toward highly functionalized 5beta-lanosterol derivatives: a versatile approach utilizing anionic cycloaddition.

Stereoselective synthesis of the potentially biologically valuable 5beta-lanosteroidal-type backbone was achieved via anionic cycloaddition. Synthesis of the two new bicyclic Nazarov intermediates 14 and 40 and their cycloaddition with chiral cyclohexenone 25 and further functional group manipulations resulted in highly functionalized tetracyclic intermediates 28 and 44. These synthetic intermediates could lead to the total synthesis of new lanosterol-based inhibitors.