A Delicate Balance of Energetics. Subtleties Associated with α-Ketol-Based Bridge Migration To Afford 9-Keto-10β-<i>p</i>-methoxybenzyloxytaxanes

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The convergent, stereocontrolled synthesis of enantiopure stereoisomeric 9,10-cyclic acetals, whose designed role was to serve as potential precursors to Taxol, is reported. These advanced intermediates are multiply functionalized and carry a bridgehead alpha-ketol array which was key to isomerization into the proper framework. In agreement with relative strain energy values obtained by MM3 calculations, a dichotomy was observed between these two families. While the trans-fused acetals failed to undergo bridge migration, their cis counterparts did so efficiently. In fact, isomerization was sufficiently rapid that oxygenation at C2 was now precluded. The operation of several unusual transannular hydride shifts is also detailed.

Section: Resultssupporting

confidence: 71%

“…Neither scenario is conducive to a concise synthesis of Taxol. In the following paper, additional subtleties associated with this chemistry are presented and a workable advance involving a favorable rearrangement arising from a derivative of 39 (where it appears as 3 ) is therein documented.…”

Section: Resultsmentioning

confidence: 99%

Effect of 9,10-Cyclic Acetal Stereochemistry on Feasible Operation of the α-Ketol Rearrangement in Highly Functionalized Paclitaxel (Taxol) Precursors

Paquette

Hofferberth

2003

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“…In our synthetic effort directed toward Taxol, we targeted a short route that was also sufficiently flexible to permit practical access to analogues. The combined application of anionic oxy-Cope and α-ketol rearrangements has been shown to fulfill our early expectations in that a convergent route from enantiomerically pure 1 to tricyclic diketone 2 has been realized in only 15 steps and 5.7% overall yield. , This notably efficient pathway also allows for incorporation of the absolute configuration of (+)-camphor into the target compounds. In light of the high level of substitution in 2 and the essentially complete overlay of its stereocenters with those resident in Taxol ( 5 ), the former was considered to be a good candidate for forward progress.…”

mentioning

confidence: 61%

Chemical Modification of a Highly Functionalized Taxane. The Consequences of an Absent Bridgehead Double Bond on Oxetane D-Ring Construction

Paquette

2003

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An oxetane D-ring has been fused to the framework of the highly functionalized taxane 2. The synthetic route is based on a trimethylsilyl triflate-promoted epoxide-opening step, followed by stereocontrolled, regioreversed oxirane formation and reductive transposition of this intermediate with bis(cyclopentadienyl)titanium(III) chloride. This last key step provides for the convenient implementation of additional hydroxyl groups ultimately conducive to intramolecular S(N)2 reaction. Tangential features of the route outlined herein include specific rearrangement reactions and a retro-aldol cleavage of ring A.

“…A direct consequence of the continuing role of Taxol ( 5 ) as an important resource in the battle against cancer is the inspiration for the development of improved new synthetic routes to the parent drug as well as to structural analogues thereof. This high level of interest has spilled over to our laboratories where the goal for several years has been to develop an approach based on the readily available (+)-camphor derivative 1 that is more abbreviated than any of the six prior completed syntheses of this powerful cytotoxic agent. − To the present time, 1 has been successfully transformed in 15 steps and 5.7% overall yield to 2 , to which an oxetane D-ring has been fused as in 3 with an outlay of only six more transformations (Scheme 1) . Already quite apparent at this point is the essentially complete overlay of functionality and stereocenters in 3 and the ultimate target 5 .…”

Section: Introductionmentioning

confidence: 96%

Diosphenol-Based Approach to the A-Ring Functionalization of Advanced Taxol Precursors

Kreilein¹,

Hofferberth²,

Hart³

et al. 2006

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Several different approaches to the A-ring functionalization of an advanced, highly functionalized diosphenol precursor to Taxol are described. The first phase of the undertaking consists of an assessment of those reagents conducive to reaction at the enolic oxygen (silylation, methylation, allylation, and acylation). Transformations involving an alternative attack at the enol carbon center (bromination, selenation) have also been defined. Sodium borohydride reduction operates from the beta-face of C-14 as long as the C-1 hydroxyl is not protected so as to offer steric exclusion. Complications associated with various aspects of these methodological undertakings are addressed. The most advanced oxygenation achievements were realized by way of a noteworthy sequence involving epoxidation of the O-methyl ether, methanolysis under mildly acidic conditions, and regioselective oxidation of diol 38 to give 39.