The Pinene Path to Taxanes. 4. Approaches to Taxol and Taxol Analogs through Elaboration of Aromatic C-Ring Precursors

Abstract

The chemotherapeutic agent Taxol (3, Scheme 1), originally obtained from Pacific yew tree bark, has shown remarkable promise in the treatment of both breast and ovarian cancer. 2 As part of our ongoing research in this area, we have developed a strategy for the synthesis of taxanes based on pinene (1), 3 which provides concise, enantiomerically controlled access to the tricarbocyclic taxane core (e.g., 2a in six steps), structural analogs, and taxol itself. 4 A recently introduced C9-C10 linker variant of this strategy has also provided tricycle 2b in only seven steps from pinene (1). 5 Herein we describe the next phase of this program, the elaboration of 2b toward both taxol and its analogs entailing concise solutions for the functionalization of the B and C rings.The elaboration of 2b began with protection of its C13 hydroxyl group as the TBS ether (4, Scheme 2). It is a noteworthy consequence of the striking interconnectedness of functional group reactivities in this structural series that 4 failed to undergo C1 deprotonation and oxidation under conditions in which the closely related silyl ether derivative of 2a reacted readily. 3 At the core of this reactivity difference is the C4 substituent (H vs MeO), which restricts 4 to a conformation in which the C1-CH bond is improperly aligned with the C2 carbonyl for deprotonation. Removal of this conformational constraint through saturation of the C9 center was found to resolve this problem, as demonstrated by the highly efficient conversion of the hydroboration product 5 (with t-BuOK/DMSO/O 2 in THF at -25°C) to the C1-oxidized product 6 in 96% yield. The primary alcohol of 6 was subsequently converted to the C9 ketone 7 (82%) by oxidation with Dess-Martin's periodinane 6 to an aldehyde (84%) followed by oxidative decarbonylation usingFurther elaboration of diketone 7 was initially accomplished by Birch reduction. However, complications with over-reduction of the aromatic ring prompted our selection of the C2 monoketone 8 in order to achieve better control over this reduction. For this purpose, ketone 8 (mp 149-150°C) was prepared by double reduction of 7 with sodium, followed by selective protection of the C9 alcohol and reoxidation of the C2 alcohol (53% yield over three steps). When 8 was treated with K/NH 3 /THF, the R-and -C3-stereoisomers 9a and 9b/ 9c were obtained in a ratio that was dependent on the reaction conditions and workup. Although it was possible to obtain either C3 epimer, compounds possessing the -CH configuration were selected for study since they were expected to afford greater stereocontrol over the introduction of groups at C8 and to be amenable to epimerization at a later synthetic stage. Ketone 8 was therefore selectively reduced to the -CH derivatives 9b and 9c (77% yield, along with a trace of 9a). Silyl ether 9b was readily converted to 9c upon treatment with acid.Access to our multipurpose analog precursor, enone 13, entailed initial reduction of the C2 ketone of 9c with Na in NH 3 /THF to the desired C2 alcohol stereoisomer 10 (85% y...

Stereoselective Cyclopropanation Reactions

“…7,8-Cyclopropyltaxol analogues 307 have been shown to be almost as potent as taxol in a number of biological assays . Wender has disclosed the preparation of such derivatives from enone 306 using sulfur ylide chemistry . Only one diastereoisomer was obtained in 69% yield when methylenedimethylsulfoxonium was used (eq 86).…”

“…314 Wender has disclosed the preparation of such derivatives from enone 306 using sulfur ylide chemistry. 315 Only one diastereoisomer was obtained in 69% yield when methylenedimethylsulfoxonium was used (eq 86).…”

The oxidation of 3-alkylhomophthalimide derivatives by dioxygen in alkaline media and Bischler-Napieralski reactions of cleavage-cyclisation products

“…27 Two representative homophthalimide derivatives were prepared in order to test their suitability for Bischler-Napieralski cyclisation reactions. Thus, 3,4-dimethoxy-bphenylethylamine and tryptamine were converted into the related N-substituted homophthalimide derivatives (10) and (11) respectively. Alkylation of the compound (10) with ethyl iodide gave a mixture of the mono-(12) and di-alkylated (13) products in 29% and 9% yields respectively while a similar reaction of the compound (11) using isopropyl iodide gave the expected 2-[2-(1H-3-indolyl)ethyl]-4-isopropyl-1,2,3,4-tetrahydro-1,3-isoquinolinedione (14) in 44% yield.…”

The Pinene Path to Taxanes. 5. Stereocontrolled Synthesis of a Versatile Taxane Precursor

“…Our synthesis strategy derived from our recognition that pinene ( 5 ), an abundant component of pine trees and a major constituent of the industrial solvent turpentine, could supply 10 of the 20 carbons and the chirality of the taxane core. In this strategy, verbenone ( 6 ), the air oxidation product of pinene, would be used as its dienolate for C11−C10 bond formation by alkylation or aldol procedures.…”