Tomoya Sugai

Synthesis of paclitaxel. 2. construction of the ABCD ring and formal synthesis

A formal synthesis of the antitumor diterpenoid paclitaxel (Taxol) is described. The ABC ring of paclitaxel, synthesized starting from 1,3-cyclohexanedione and tri-O-acetyl-d-glucal by SmI2-mediated cyclization as the key transformation, was successfully converted to Takahashis tetracyclic oxetane intermediate. A double Chugaev reaction was employed for introduction of the strained bridgehead olefin, and stereoselective formation of the oxetane ring afforded the known synthetic intermediate, completing the formal synthesis of paclitaxel.

Synthesis of Paclitaxel. 1. Synthesis of the ABC Ring of Paclitaxel by SmI2-Mediated Cyclization

A convergent synthesis of the ABC ring of antitumor natural product paclitaxel (Taxol) is described. SmI2-mediated reductive cyclization of an allylic benzoate possessing an aldehyde function, synthesized from tri-O-acetyl-d-glucal and 1,3-cyclohexanedione, smoothly afforded the highly strained 6-8-6 tricarbocyclic structure in 66% yield.

Crystal structure of (±)-(4RS,5RS,7SR)-4-[(1RS,2RS,3RS,6RS)-3-benzo-yloxy-2-(2-hy-droxy-ethyl)-6-meth-oxy-meth-oxy-2-methyl-cyclo-hex-yl]-8,10,10-trimethyl-2-oxo-1,3-dioxa-spiro-[4.5]dec-8-en-7-yl benzoate benzene monosolvate.

In the title compound, the ring conformations of the tricycles are in an envelope, a half-chair and a chair. In the crystal, intermolecular O—H⋯O and C—H⋯O hydrogen bonds and C—H⋯π interactions link the molecules into a three-dimensional architecture.

Practical synthesis of the C-ring precursor of paclitaxel from 3-methoxytoluene

The practical synthesis of the C-ring precursor of paclitaxel starting from 3-methoxytoluene is described. Lipase-catalyzed kinetic resolution of a substituted cyclohexane-1,2-diol, derived from 3-methoxytoluene in three steps, successfully afforded a desired enantiomer with >99% ee, which was transformed to a cyclohexenone. 1,4-Addition of a vinyl metal species, followed by Mukaiyama aldol reaction with formalin in the presence of a Lewis acid provided the known C-ring precursor of paclitaxel in a 10 g scale.

Crystal structures of (±)-(1SR,5SR,6SR,7SR,10SR,11SR,13RS,14SR)-13-hy­droxy-7-meth­oxy­meth­oxy-11,15,18,18-tetra­methyl-3-oxo-2,4-dioxa­tetra­cyclo­[12.3.1.01,5.06,11]octa­dec-15-en-10-yl benzoate, its 13-epimer and 13-one derivative

In the title three compounds, the ring conformations of tetracycles are similar; each tetracycle adopts essentially planar, chair, half-chair and chair–chair forms. In the crystals, molecules are linked into similar chains by intermolecular hydrogen bonds.

Crystal structure of (–)-methyl (R,E)-4-[(2R,4R)-2-amino-2-tri­chloro­methyl-1,3-dioxolan-4-yl]-4-hy­droxy-2-methyl­but-2-enoate

In the title compound, the 1,3-dioxane ring has an envelope conformation. In the crystal, classical O—H⋯O and N—H⋯O hydrogen bonds link molecules into a sheet structure, and a weak intermolecular C—H⋯Cl interaction extends the sheet structure into a three-dimensional network.

Crystal structure of (+)-N-[(1R,5S,6S,9S)-5-hydroxy­methyl-3,3,9-trimethyl-8-oxo-2,4,7-trioxabi­cyclo­[4.3.0]nonan-9-yl]acetamide

In the title compound, the 1,3-dioxane ring is in a chair-like conformation, while the fused oxolane ring adopts an envelope form. In the crystal, classical O—H⋯O and N—H⋯O hydrogen bonds link the molecules into a sheet structure.

Crystal structure of (±)-(7RS,8SR)-7-methyl-1,4-dioxa-spiro-[4.5]decane-7,8-diol.

In the title compound, the dioxolane and cyclohexane rings adopt twist and chair conformations, respectively. In the crystal, intra- and intermolecular O—H⋯O hydrogen bonds are observed.