Synthesis of (±)-oleocanthal via a tandem intramolecular Michael cyclization–HWE olefination

Abstract

A synthesis of racemic oleocanthal has been accomplished in eleven steps from 1,3 propanediol by a key tandem intramolecular Michael cyclization-Horner Wadsworth Emmons olefination.The secoiridoids are a class of plant-derived monoterpenes containing the substituted pyran core of secologanin (1). This class of natural products arises in biological systems from the oxidative cleavage of the loganin skeleton (2) by the cytochrome P450 enzyme secologanin synthase. 1 Secologanin then undergoes various modifications to produce a wide array of structures displaying diverse biological activity including analgesic 2 , anti-inflammatory 3 , antiarthritic4, anti-allergenic5, antibacterial6, and antiviral 7 activities. Coupling of the simple secoiridoids with tryptamine gives rise to a large class (>250 examples) of indole and oxindole alkaloids including geissoschizine, strychnine, reserpene, ajmaline, and the Vinca alkaloids with highly varied carbon frameworks and biological profiles.We reasoned that, given the structural similarities of the secologanin-derived natural products, synthetic access to the more complex secoiridoid and secologanin tryptamine alkaloids could be obtained through a single strategically functionalized intermediate. As a test case for our strategy, our attention focused on the secoiridoid oleocanthal (3) both for its relative structural simplicity which retains the compact arrangement of functionality of the secoiridoids as well as its demonstrated potency as an inhibitor of the COX-1 and COX-2 enzymes 3,8 , making it an ideal entry point into the synthesis of this class of natural products.Important to our retrosynthetic analysis was proceeding through an intermediate with functionalities that could be independently manipulated allowing for future adaptation of this synthesis to produce a diverse selection of natural product targets. Lactone 5 appeared ideal for this purpose as it contains the requisite carbon backbone as well as properly situated synthetic handles with orthogonal reactivities.We envisioned the dialdehyde moiety of 3 arising from the reduction and oxidation of lactone 5 whose carbon framework could be assembled through a key tandem Michael cyclization and Horner-Wadsworth-Emmons (HWE) olefination 9 of phosphonoacetic ester 6. This allows for the simultaneous assembly of the desired lactone core, the addition of the two-carbon olefin sidechain, and the introduction of a stereogenic center. Studies to control the absolute configuration of this new stereogenic center through the introduction of chiral auxiliaries are currently underway. Assembly of lactone 5 began with the synthesis of aldehyde 7 from 1,3-propanediol utilizing the method reported by Schaus and coworkers. 10 Reaction of 7 with commercially available trimethyl acetophosphonate under Masamune-Roush conditions produced the unsaturated ester 8 as a single isomer and in good yield (Scheme 2). Deprotection and subsequent esterification gave the desired substrate 6, which upon treatment with Cs 2 CO 3 and acetaldeh...

A Synthetic and Computational Investigation into the Direct Synthesis of ?-Hydroxymethylated Enones from ?-Keto Phosphonates

“…Alternatively, intermediate 5 may directly fragment to afford olefin 3, which then undergoes MBH reaction catalyzed by β-keto phosphonate 2 to provide alcohol 1 directly (pathway B), or by enone 4 (pathway C). [9] The failure of the least hindered substrates 2f, j, k, and l to afford any by-products would appear to suggest that the reaction occurs by a mechanism sensitive to sterics, which supports the originally proposed pathway A. Potentially, pathways B and C become operative in cases where steric crowding slows the formation of intermediate 6.…”

“…Alternately, the formation of such by-products may be explained by the initial formation of enone 3a, which is subsequently converted into allylic alcohol 1a by a MBH reaction catalyzed by phosphonate 2a. [9] In this case, the formation of 4a would arise as a result of dehydration of a MBH intermediate, rather than elimination of phosphonate 2a (Scheme 4).…”

Preparative isolation of oleocanthal, tyrosol, and hydroxytyrosol from olive oil by HPCCC

“…For in vivo studies, higher amounts of the compound are needed. The synthesis of OLC requires about ten steps and the yields remain quite low (Smith, Sperry & Han, 2007;English & Williams, 2009;Takahashi, Morita & Honda, 2012;Valli et al, 2013). Thus, isolation of OLC from natural sources (olive oil, olive oil pomace, olive leaves or olive oil mill waste water) is an important option.…”

A Concise and Efficient Total Synthesis of Oleocanthal

“…In fact, besides the pioneering work of A. B. Smith III and collaborators,2 the only other synthesis completed so far was through a tandem intramolecular Michael cyclization/Horner–Wadsworth–Emmons olefination, which afforded racemic 1 11a. In addition, two formal syntheses appeared recently, which made use of a Johnson–Claisen (orthoester) rearrangement strategy11b and an SmI 2 ‐promoted intramolecular coupling of bromoalkyne with α,β‐unsaturated ester,11c respectively.…”