Stereospecific Anionically Promoted Transannular Hydride Shifts in Medium-Ring Hydroxy Ketones. Probe of Their Reversibility and the Potential for Regiocontrol

et al. 2003

J. Org. Chem.

Self Cite

The feasibility of the title reaction has been pursued for the purpose of advancing a concise total synthesis of Taxol. Of the two closely related series examined, the first featured an exo-methylene group at C4. The second consisted of an alpha-epoxide at that site. Strikingly, the olefinic construct proved inert to attempted alpha-ketol rearrangement. In contrast, the oxiranyl derivative isomerized smoothly. The reaction sequence associated with arrival at taxane 18 is short (15 steps from a D-camphor derivative) and notably efficient. The thermodynamic issues that are raised by this investigation have been clarified by an assessment of molecular mechanics-derived (MM3) steric energy calculations.

Section: Resultsmentioning

confidence: 99%

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

et al. 2003

J. Org. Chem.

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“…The structural assignments to both 29 and 30 were confirmed by three-dimensional crystallographic analysis …”

Section: Methodsmentioning

confidence: 75%

“…To improve the efficiency of the aldol cyclization, possible catalysis by several other bases was screened. The use of 0.5 N NaOH in 2.3:1 methanol/THF was met not only with a doubling of efficiency but was also accompanied by formation of a 6:1 mixture of 29 and the transannular hydride shift product 30 (Scheme ) …”

Section: Resultsmentioning

confidence: 99%

“…In final optimized form, the conversion of 27 to 30 can be performed in a single operation in nearly quantitative yield, providing material of sufficient purity for use in subsequent steps without recourse to chromatography. Crystallographic data are available for both 29 and 30 4 …”

Section: Resultsmentioning

confidence: 99%

“…The use of 0.5 N NaOH in 2.3:1 methanol/THF was met not only with a doubling of efficiency but was also accompanied by formation of a 6:1 mixture of 29 and the transannular hydride shift product 30 (Scheme 4). 21 In an important development, the discovery was made that potassium tert-butoxide in benzene is capable of bringing about the wholesale conversion of 29 to 30. In final optimized form, the conversion of 27 to 30 can be performed in a single operation in nearly quantitative yield, providing material of sufficient purity for use in subsequent steps without recourse to chromatography.…”

Section: Resultsmentioning

confidence: 99%

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

2003

J. Org. Chem.

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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.

The α‐Hydroxy Ketone (α‐Ketol) and Related Rearrangements†

2003

Organic Reactions

Treatment of suitable alpha‐hydroxy aldehydes and ketones with a base, a Bronsted or Lewis acid, or simply with heat has long been know to induce the 1,2‐shift of an alkyl or aryl substituent to form an isomeric product. The synthetic utility of the process was considerably expanded when applied to steroidal D‐ring homoannulations, and has more recently encompassed novel ring expansion to numerous complex target ring systems. The classical alpha‐ketol rearrangement shares, in common with other base‐promoted ketogenic isomerizations, the property of advancing from an alkoxide to a carbonyl group as the migrating center relocates its bonding electrons to the adjacent trigonal center. A distinctive feature of the title reaction, however, is its reversibility, such that the more stable alpha‐hydroxy carbonyl isomer is favored. The process has sometimes been termed the acyloin rearrangement. This chapter focuses on the isomerization of alpha‐hydroxy ketones, aldehydes, and imines under various reaction conditions exclusive of photochemical activation. The literature coverage extends to 2000. Since many of the steroidal transformations were carried out in early days when products were not always adequately characterized; errors in structural assignment were occasionally made. Experimental detail was sometimes lacking. To alleviate this problem, we have included only experiments that lead to reasonably pure products of established structure.