Charles S. Swindell

NMR and molecular modeling study of the conformations of taxol and of its side chain methylester in aqueous and non-aqueous solution.

Abstract The conformations of the antimitotic agent taxol and its side chain methyl ester have been studied by NMR-spectroscopy and molecular modeling in hydrophobic (CDCl3) and hydrophilic (water, d6-DMSO) solvents. For the side chain methyl ester (4), the coupling constant JH2′-H3′ changes from ≈2 Hz in chloroform to ≈5 Hz in d6-DMSO or water : d6-DMSO, 1 : 1 (v/v). The conformational equilibrium for 4 thus shifts from one favoring conformers with a gauche torsion angle (chloroform), to one predominantly of conformers having this torsion angle anti. In the case of taxol, JH2′-H3′ changes from 2.7 Hz in CDCl3 to ≈8 Hz in water, water - sodium dodecyl sulfate (SDS) and/or d6-DMSO. Again, gauche conformations are implicated in chloroform, but molecular modeling suggests the anti conformer 27 to be dominant in aqueous media and in d6-DMSO. No nuclear Overhauser effects (nOes) between the side chain and the taxane ring-system are observed in chloroform solution. In water and/or d6-DMSO, however, nOes between the side chain (Ph3′ and H2′) and the OAc4 methyl group are detected.

Regio- and stereochemistry of the intramolecular [2+2] photoproducts from two related vinylogous imides

Abstract The regio- and stereochemistry of the intramolecular [2+2] photoproducts from two related vinylogous imides have been determined with the aid of X-ray crystallography; their chemistry and a mechanistic rationale of their formation are presented.

Construction of an advanced taxane synthesis intermediate with an oxygenated B-ring and a non-aromatic C-ring through intramolecular pinacol coupling at C-1C-2

Advanced taxane synthesis intermediate 4 is available through a thirteen-step sequence wherein the key step is a stereoselective intramolecular pinacol coupling that joins C-1ue5f8C-2 within the eight-membered B-ring.

Synthesis and stereochemistry of a saturated tricyclic taxane model

Abstract The construction through an A-ring annulation strategy of a fully B-ring methylated saturated tricyclic taxane model and the demonstration of its preference for trans BC ring junction stereochemistry are described.

Characterization of the taxol structure-activity profile for the locus of the A-ring side chain

Abstract Two series of taxol analogs with various N -acyl groups on 3′-phenylisoserine and isoserine A-ring side chains, respectively, were prepared, and their microtubule assembly acitivities and cytotoxicities toward J774.2 cells were evaluated. Biological activities were adversely affected by the structural modifications investigated, although the 3′-phenylisoserine series was significantly more active than the isoserine series.

Bicyclo[5.3.1]undec-1(10)-ene bridgehead olefin stability and the taxane bridgehead olefin

Abstract MM2 calculations have shown how substituent and conformational effects play a role in the stabilities of systems containing the bicyclo[5.3.1]undec-I(10)-ene moiety and that the taxane diterpene skeleton which possesses this structural feature is surprisingly stable.

Pinacol closure of oxygenated taxane skeleta at C-1-C-2 with stereoinduction by oxygen substituents at C-9 and C-10

The treatment of keto aldehydes 4 and 5 with low-valent Ti results in stereoselective intramolecular pinacol couplings that lead to optically active oxygenated taxane skeleta 2 and 3.

An AC→ABC approach to taxol involving B-ring closure at C-1-C-2

Abstract The treatment of keto aldehyde 13 with low-valent Ti results in a stereoselective intramolecular pinacol coupling that produces taxane synthesis intermediate 14.

Evaluation of a chiral aryl auxiliary design for sulfur: construction of auxiliary-modified reagents and stereoselection in sulfoxide formation

Compounds possessing thiol, sulfide, and sulfoxide functionality attached to chiral auxiliary fragment 1 can be synthesized from halogenated aromatics 2 and 3. In the sulfoxides,auxiliary 1 can define the sulfinyl configuration in either relative sense depending on whether sulfinyl configuration is established under kinetic or thermodynamic control.

TAXANE SYNTHESIS THROUGH INTRAMOLECULAR PINACOL COUPLING AT C-1-C-2. CONSTRUCTION AND OXIDATIVE TRANSFORMATIONS OF A C-AROMATIC TAXANE DIENE

A ten-linear-step construction of C-aromatic taxane diene 14 from ethyl isopropyl ketone, acryloyl chloride, and commercially available 8 is reported. This sequence concludes with an intramolecular pinacol coupling carried out on 13. 14 is oxidized by m-chloroperbenzoic acid and dimethyldioxirane to give 17 through intermediate epoxide 20 and by VO(acac)2−t-BuOOH and Mo(CO)6−t-BuOOH to give 13. 17 is converted efficiently into 22 upon treatment with Mo(CO)6−t-BuOOH, apparently through an unusual equilibration with isomeric 20, which is converted irreversibly to 22. While these oxidative transformations highlight some of the peculiar reactivity patterns characteristic of taxane-related structures, the formation of 14 through an intramolecular pinacol coupling that joins C-1 and C-2 demonstrates the potential of this strategy for stereoselectively delivering advanced taxane synthesis intermediates.