ConspectusAn ortho-quinone methide (o-QM) is a highly reactive chemical motif harnessed by nature for a variety of purposes. Given its extraordinary reactivity and biological importance, it is surprising how few applications within organic synthesis exist. We speculate that their widespread use has been slowed by the complications that surround the preparation of their precursors, the harsh generation methods, and the omission of this stratagem from computer databases due to its ephemeral nature.About a decade ago, we discovered a mild anionic triggering procedure to generate transitory o-QMs at low temperature from readily available salicylaldehydes, particularly OBoc derivatives. This novel reaction cascade included both the o-QM formation and the subsequent consumption reaction. The overall transformation was initiated by the addition of the organometallic reagent, usually a Grignard reagent, which resulted in the formation of a benzyloxy alkoxide. Boc migration from the neighboring phenol produced a magnesium phenoxide that we supposed underwent β-elimination of the transferred Boc residue to form an o-QM for immediate further reactions. Moreover, the cascade proved controllable through careful manipulation of metallic and temperature levers so that it could be paused, stopped, or restarted at various intermediates and stages. This new level of domestication enabled us to deploy o-QMs for the first time in a range of applications including diastereocontrolled reactions.This sequence ultimately could be performed in either multipot or single pot processes. The subsequent reaction of the fleeting o-QM intermediates included the 1,4-conjugate additions that led to unbranched or branched ortho-alkyl substituted phenols and Diels–Alder reactions that provided 4-unsubstituted or 4-substituted benzopyrans and chroman ketals. The latter cycloadducts were obtained for the first time with outstanding diastereocontrol. In addition, the steric effects of the newly created stereocenters in subsequent reactions of chroman ketals and acetals were studied and proved predictable. Through the use of a chiral auxiliary, Diels–Alder products were deployed in numerous enantioselective reactions including several complex natural products syntheses. In this Account, we summarize our efforts, which we hope have contributed to the synthetic renaissance for this venerable species.

An expeditious convergent total synthesis affords (±)-γ-rubromycin (1) in 4.4% overall yield. The longest linear sequence is 12 steps from commercial starting materials. The effort highlights a remarkable late-stage oxidative [3 + 2] cycloaddition for construction of the spiroketal, a regioselective carbonyl methylenation, a boron tribromide promoted deprotection, ortho- to para- naphthoquinone spiroketal rearrangement, and a tautomerization sequence.

A variety of chroman spiroketals are synthesized via inverse-demand [4 + 2] cycloaddition of enol ethers and ortho-quinone methides (o-QMs). Low temperature o-QM generation in situ allows for the kinetic, diastereoselective construction of these motifs, providing entry to a number of unusual chroman spiroketal natural products.Aliphatic spiroketals are a common substructure of natural products isolated in a large variety from both marine and terrestrial sources. 1 Studies aimed at understanding the origins of their conformational preference have resulted in the general assumption that the spiroketal carbon corresponds to the thermodynamically most stable isomer as determined by stereoelectronic influences. Hence, the biosynthesis of these fluxional natural products usually results in the construction of the most stable diastereomer or a mixture that reflects energy differences between respective diastereomers.For some time, we have speculated that a rare subset consisting of chroman spiroketals (1, 2 2 ,3 and 3 ,4 Figure 1) may possess features that refute this basic tenet and require a kinetic assembly. These uniquely robust chroman spiroketal scaffolds have caused us to consider new methods for their construction.Some time ago, we developed a method that enables the controlled, low-temperature generation of o-quinone methides (o-QMs) (Figure 2, I). 5 The process, which is driven by the relative stability of sequential anions formed along the cascade, begins by formation of an alkoxide. This species intercepts a neighboring carbonyl of a phenolic carbonate and thus liberates a phenoxide that subsequently undergoes β-elimination of a carboxylate and thereby forms a reactive o-QM species, which captures the first nucleophile that it subsequently encounters. This is a useful method for o-QM generation because, since the reactive o-QM intermediate is generated at low temperature in low concentrations, it subsequently participates in very precise, kinetically controlled reactions. 6 Using this procedure, we demonstrated the first examples of diastereoselective o-QM cycloadditions and found that the inverse demand [4 + 2] significantly favors an endo transition state with electron-rich alkenes. 7 In further experiments, we showed that chiral enol ethers containing remote stereocenters, such as those derived from (1S,2R)-2-phenyl-cyclohexanol, will participate in diastereoselective cycloadditions to yield the corresponding chroman acetals with an R configuration (Figure 2, II) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript R 1 , R 2 , and R 3 substituents should also participate in cycloadditions with similar diastereoselectivity (Figure 2, III). Detailed analysis of our proposed transition state allowed us to further speculate that substituents R 1 and R 3 would have a pronounced effect on the stereochemical outcome, whereas the R 2 residue would not, allowing it to be tolerated on the same face as the reaction. Therefore, we began to examine model systems that might eventually be ...

Despite intense academic and industrial efforts and innumerable in vitro and cell studies, no small-molecule telomerase inhibitors have emerged as drugs. Insufficient understanding of enzyme structure and mechanisms of interdiction coupled with the substantial complexities presented by its dimeric composition have stalled all progress toward small-molecule therapeutics. Here we challenge the assumption that human telomerase provides the best platform for inhibitor development by probing a monomeric Tetrahymena telomerase with six tool compounds. We find BIBR-1532 (2) and MST-312 (5) inhibit only human telomerase, whereas β-R (1), THyF (3), TMPyP4 (6), and EGCG (4) inhibit both enzymes. Our study demonstrates that some small-molecule scaffolds can be easily surveyed with in vitro studies using Tetrahymena telomerase, a finding that could lead to more tractable inhibitors with a greater potential for development given the more precise insights that can be gleaned from this more easily expressed and assayed monomeric enzyme.

A highly selective oxidative [3 + 2] cycloaddition of chiral enol ethers and hydroxynaphthoquinone is described. This convergent strategy is amenable to an enantioselective synthesis of β-rubromycin and related naphthoquinone spiroketals. Several compounds were found to inhibit DNA-polymerase and telomerase in a manner resembling α-rubromycin and β-rubromycin.(+)-β-Rubromycin belongs to a unique family of optically active spiroketal natural products with a rich and emerging history ( Figure 1). 1 Brockmann first isolated α-rubromycin (1), β-rubromycin (2a), and γ-rubromycin (3) in 1966 from strains of Streptomyces collinus bacteria. 2 However, Zeeck later revisited the structure in 2000 and assigned it as the p-quinone (2b). 3 With assistance from Bringmann, an S-configuration was assigned to the unique spiroketal in 2b using circular dichroism. 4 β-Rubromycin (2b) and γ-rubromycin (3) inhibited telomerase with an IC 50 of less than 3 µM. 1 On the other hand, α-rubromycin (1) proved inactive (IC 50 > 200 µM), exhibiting efficacy well outside the window of the assay. 1 Because of this discrepancy between 1 and 2 and 3, Hayashi proposed that the spiroketal moiety found in the structure of the inhibitors was responsible for their efficacy and as a privileged structural component offered a good starting point for synthetic chemists.From a synthetic perspective, rubromycins (2 and 3) pose several interesting questions. 1 These molecules are presumably biosynthesized as single enantiomers. However, each contains a single spiroketal stereocenter. Therefore, these compounds do not appear to be biosynthesized by a conventional thermodynamic ketalization. Nevertheless, the universal strategy has been to anneal two components together about a centralized carbonyl moiety. 5 Researchers synthesized lower oxidation surrogates of the naphthoquinone moiety, such as naphthazarin and benzyloxy derivatives. Most have reported methods to anneal these fragments together. 6 Despite several extraordinary efforts, only Danishefsky and co-workers reported synthesizing a naphthoquinone-isocoumarin spiroketal, albeit the aglycone of heliquinomycin. 7 However, their nontraditional spiroketalization method is not easily adapted to the synthesis of 2 and 3. 8 We therefore thought thermodynamic spiroketalization of compounds 2 and 3 was an unsound strategy.We imagined instead that a p-naphthoquinone spiroketal could be produced in a single kinetic step amenable to diastereoselective control whereupon the stereochemistry that directed the formation of the spiroketal stereocenter could be erased (Figure 2). The [3 + 2] oxidative cycloaddition initially observed by Roy and Mandal could be used to test our plan. 9 pettus@chem.ucsb.edu. Supporting Information Available: Experimental procedures and key spectral data for all new isolable compounds 5, 7-9, and 14-16. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe...