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 C2-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 C2 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 SN2-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. The glycosylation stereoselectivity is then governed by the displacement of the weaker bent bond as determined by the presence of electron-withdrawing or -donating substituents at C2. Overall, the BBAH analysis expands Woerpel's "inside/outside attack" glycosylation model by considering the stereoelectronic influence of neighboring electron-withdrawing and -donating groups on the nucleophilic addition to oxocarbenium ion intermediates.

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. The BBAH dictates that allyl diradical intermediates, produced during methylenecyclopropane thermolysis, retain pyramidal character due to antiperiplanar delocalization into their respective bent bond.

Bent Bonds (τ) and the Antiperiplanar Hypothesis-The Chemistry of Cyclooctatetraene and Other C8H8 Isomers.

The bent bond/antiperiplanar hypothesis (BBAH) has been applied to the thermal rearrangements of cyclooctatetraene and related C8H8 isomers. This novel orbital model shows that pyramidal singlet diradical intermediates produced from thermal vibrational states of C8H8 isomers account for their chemical reactivity.

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.

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). For example, 13C-1-naphthalene is specifically converted to 13C-2-naphthalene, and there is evidence that this occurs through the formation of benzofulvene and a naphthalene-carbene intermediate. Application of the bent bond/antiperiplanar hypothesis leads to the postulate that higher in energy pyramidal singlet diradical intermediates can be used to propose a mechanism that rationalizes various atom rearrangements on benzenoid aromatics and related isomeric compounds.

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. This accounts for the preference of suprafacial rearrangement pathways as well as the extent of inversion or retention of configuration at the migrating carbons.

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 C2-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.

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 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.

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. The bent bond model and the antiperiplanar hypothesis provide a qualitative model for better understanding the electron delocalization and the reactivity inherent to unsaturated organic systems by an alternative view of the classic resonance theory.

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. Following extensive optimization, the coupling of 3 on both ends with another densely functional partner 2 followed by TADA reaction on macrocycle 4 cleanly furnished the tricycle 5. The stereochemical outcome in 5 was expected via a least-energetic transition state T4. A stereoselective reduction, hydroboration, and methyl cuprate 1,4-addition along with a few other functional interconversions transformed 5 into the key intermediate 37. Final tethering of dimethylaminoethyloxycarbonyl along with epimerization at C8 and alcohol deprotection at C3 yielded the natural product 1.

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.

Nazarov reagents for convergent and expedient synthesis of new steroids.

[reaction: see text] A new methodology for the convergent synthesis of tetracyclic compounds was developed. Two new bicyclic Nazarov reagents of type II were synthesized, and their cycloaddition with 2-carbomethoxy-2-cyclohexenone I was studied. This cycloaddition afforded new interesting steroidal backbones.

Comparative effects of conjugated and deconjugated isomeric enones on the transannular Diels-Alder reaction.

Two isomeric cyclic trienones 2 and 3 (with four methyl esters at positions 3 and 10) underwent transannular Diels-Alder (TADA) reaction at very different temperatures. This drastic difference could be traced to the capacity of the enone dienophile to be conjugated or unconjugated at the transition state. Molecular modeling could confirm this explanation. The calculated enone proved to be very distorted in transition state ts2, and the TADA reaction temperature was accordingly much higher than the one corresponding to ts3 in which the enone was flat. [reaction: see text]

Hydrolysis of alpha- and beta-glycosides. New experimental data and modeling of reaction pathways.

[reaction: see text] The cyclization of oxocarbenium ion conformers 6alpha and 6beta (from 11E and 11Z) gave only the beta-glycoside 1beta, and the addition of methanol to the oxocarbenium ion 3 yielded mainly the alpha-glycoside 1alpha with both experiments being carried out under kinetically controlled conditions. RHF/6.31G calculations reproduce well these experimental results and show that the endocyclic and the exocyclic C-O bond cleavage processes can compete in the hydrolysis of 1beta, whereas 1alpha gets hydrolyzed by exocyclic C-O bond cleavage only.

Studies directed toward asymmetric synthesis of cardioactive steroids via anionic polycyclization.

[reaction: see text] The use of anionic polycyclization (AP) in constructing the steroidal backbone of cardenolides was investigated. The reaction of 2-carbomethoxy-2-cyclohexenone I with the enolate of Nazarov reagent II gave, after decarboxylation and aldol condensation, steroid III with control of stereochemistry.

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. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure-activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-ß hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1.