John Haseltine

A CONVERGENT SYNTHESIS OF (+)-PANCRATISTATIN BASED ON INTRAMOLECULAR ELECTROPHILIC AROMATIC SUBSTITUTION

Abstract A convergent formal synthesis of (+)-pancratistatin ( 1 ) is reported. Specifically, an optically active adduct of piperonyl bromide and acetonated conduritol A was converted to a late-stage intermediate from the Danishefsky-Lee synthesis of 1 . The carbon skeleton was established via intramolecular electrophilic aromatic substitution within the piperonylated conduritol. Some competitive cationic rearrangement was observed in this operation, being dependent on the degree to which a 2-substituent in the piperonyl domain favors attack ipso to the piperonyl benzylic carbon.

Simple Preparations of Tricyclic Orthoamides and Macrocyclic Triamines

Abstract Hexahydropyrimidopyrimidine 3 is condensed with an alkyl ditosylate 4 at room temperature in DME or toluene. The resulting tricyclic salt is reduced with sodium borohydride to provide orthoamides 6a-c. Acidic hydrolysis of these orthoamides gives the corresponding macrocyclic triamines 8a-c in high yield.

A novel case of cationic rearrangement involving a phenonium ion

Abstract A cationic rearrangement was observed in the intramolecular electrophilic substitution of a trioxygenated benzyl ether. The crystal structure of the product is presented.

Toward (+)-pancratistatin: Modulation of mechanism in an intramolecular electrophilic aromatic substitution

Abstract Triflation of the allylic alcohol of a piperonylated conduritol (4) induces intramolecular electrophilic alkylation of the piperonyl aromatic ring. The regiochemistry of attack relative to the tethering element (ortho vs. ipso) and therefore the distribution of products are controlled by the identity of an arene substituent (Z in 4). Advanced intermediates for the synthesis of anticancer agent (+)-pancratistatin are obtained.

Asymmetry and dynamics in bis-intercalated DNA

The bis-intercalator ditercalinium (NSC 366241), composed of two 7 H-pyridocarbazoles linked by a bis(ethylpiperidinium), binds to DNA with a binding constant greater than 10(7) M-1. One distinctive aspect of the 3-D X-ray structure of a DNA-ditercalinium complex is its asymmetry. We propose here that the activity of ditercalinium may be related to structural polymorphism and dynamic conversion between conformers. It was previously reported that activity is closely related to linker composition. Activity increases with increasing conformational restraints of the linker. We suggest these conformational restraints can lead to asymmetry in DNA complexes and that this asymmetry results directly in structural polymorphism. Using the Cambridge Structural Database (CSD) as a source of information about chemical fragments that are analogous to the linker of ditercalinium, we have explored the conformational space available to ditercalinium. The results indicate that the linker is highly constrained and that the DNA complex is intrinsically asymmetric. We propose a reasonable mechanism of ring reversal that is consistent with the conformations of analogous fragments within the CSD.

Interactive n→σ∗ delocalizations that control an aqueous organic equilibrium

Abstract Hydrated acetaldehydes were condensed in D 2 O with substituted alcohols and thiols to determine ΔG of hemiacetalization by 1 H NMR. Specific n→σ ∗ delocalizations in the alkoxy/alkylthio functionality of the product interact to influence n→σ ∗ delocalization in the hemiacetal functionality. Delocalization in the latter functionality controls ΔG.

Double Cationization with Alkali Ions in Liquid Secondary Ion Mass Spectrometry

Abstract A unique double cat ionization process produces a singly charged ion (M+2Met)+in the LSIMS mass spectra of nitro-group containing organic molecules. In contrast to the usual replacement of a hydrogen by the second metal atom to form (M+2Met-H)+, there is no loss of hydrogen in the doubly cationized species. Since two positively charged metal ions are added to the neutral sample molecule, a one-electron reduction step must also be invoked. Product ion MS/MS spectra suggest that both metal cations are associated directly with the nitro group. For the nitro-group containing compounds studied, the double cat ionization production is preferentially formed with cesium and any other group I metal ion.

Ion-Pair Cationization Process in Liquid Secondary Ion Mass Spectrometry

Positive-ion fast atom bombardment (FAB) or liquid secondary ion mass spectra (LSIMS) typically provide the molecular mass of the organic sample M via the presence of a dominant protonated molecule (M+H)+ in the mass spectrum. In addition to the proton transfer reaction, cationization processes result in the formation of ions (M+Met)+, in which the metal is derived from metal salts present in the sample as impurities or purposefully added as promoters to the sample solution. Group I metal salts (lithium, sodium, and potassium salts are popular, but rubidium and cesium salts can also be used) result in cationized ions (M+Li)+, (M+Na)+, and (M+K)+. These ions provide multiple confirmations of the molecular mass M of the sample compound. Cationization reactions (as generalized Lewis acid/base reactions) are encountered not only in FAB and LSIMS but also in other desorption ionization methods of mass spectrometry, including field desorption (FD) mass spectrometry. Traditionally, cationization is considered to be the result of the addition of one singly charged metal ion to the neutral sample molecule. If the initial charge state of the metal ion is that of Met2+ or Met3+, the cationized form of the sample molecule observed in the mass spectrum is usually the singly charged species (M+Met)+, and an electron reduction must have occurred. For incorporation of two metal cations, there is always a concomitant loss of hydrogen to form, as an example, (M+2Met-H)+. Recent studies have re-examined the details of the cationization process. For instance, recent work has shown that when the organic sample molecule contains a nitro substituent, a cationization process can occur to form a singly charged ion that contains two alkali ions, viz., (M+2Met)+. The present work highlights yet another form of the cationization reaction.