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A new general process for constructing ortho-tert-butyl phenols is presented within the context of other known methods. All are briefly evaluated with regards to regioselectivity, efficiency, and functional group tolerance. In addition, we present an assortment of tert-butyl substrates accessed through o-QM chemistry. Our conclusion is that the o-QM process provides greater yields, flexibility, and generality than most other known methods for delivering ortho-tert-buytlated phenols and their derivatives.1 Introduction2 Friedel–Crafts Alkylation3 Addition of t-Bu– or t-Bu• to Carbonyl Compounds4 ipso-SNAr Reactions of Aryl Methoxy and tert-Butylsulfoxide Moieties5 Metal-Mediated Coupling of Aryl Bromides6 Applications of o-Quinone Methides (o-QMs)7 Conclusion

A one-pot method for joining three separate components leading to an assortment of N-substituted 3,4-dihydro-2H-1,3-benzoxazines is described. The method involves the addition of a Grignard reagent to an o-OBoc salicylaldehyde in the presence of an imine. With a variety of components, 15 examples are presented, including the diastereoselective incorporation of chiral imines.

The tetrapetalones were pursued for well over a decade by numerous research groups. Herein, we detail our motivations and findings, which we imagine are very different from the many others who tackled this extremely challenging problem. In this chapter, we explain how our many failures caused us to revise our strategy eight times. Although we failed to reach the genuine natural product, we hope the reader will conclude that we nevertheless developed several valuable methods and that we gained important strategic insights from our trials and tribulations. At the very least, we can emphatically state that we developed a great appreciation of the wonderful ways in which our chemistry community is interconnected, and the great benefit we all enjoy from one another's achievements.

A strategy toward tetrapetalones was explored including a site-selective ethylenation of the silyl enol ether A to afford a quaternary stereocenter that serves in a stereogenic capacity. Regio- and diastereoselective reactions were observed in conjunction with the oxidative formation of cation B, which included subsequent selective formation of either carbon-oxygen or carbon-carbon bonds at the δ or ζ position on the seven-membered ring. The fourth ring was formed using a Stetter reaction.

A one-pot method for joining three separate components leading to an assortment of N-substituted 3,4-dihydro-2

The carbon framework of des-hydroxy paecilospirone was rapidly synthesized using a biomimetic approach whereby an enol ether and an ortho-quinone methide (o-QM), each derived from the same lactone, were combined to arrive at the complete carbon skeleton of paecilospirone.

The total syntheses of medicarpin, sophoracarpan A, and kushecarpin A from a common intermediate are achieved by using ortho- and para-quinone methide chemistry. Additionally, the relative stereochemistry of sophoracarpan A and B have been reassigned.

CONSPECTUS: An 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.

A catalytic diastereoselective aldol reaction has been developed for N1-arylated/C2-O-silylated/C3-methylated and brominated/C4-O-methylated pyrroles in its reactions with various aldehydes. Syn adducts emerge with regard to the vicinal nitrogen and oxygen heteroatom substituents. The N1-aryl residue undergoes oxidative cleavage, and the C3-bromine atom undergoes palladium-mediated coupling reactions, both without disturbing the newly created stereocenters.

Synthetic access to regiodifferentiated meta-amino phenols is described. The strategy relies upon distinct deprotonation conditions to afford regioisomeric thermodynamic and kinetic dienes that undergo a tandem Diels–Alder and retro-Diels–Alder sequence with assorted acetylenic dienophiles to afford a range of aromatic products.

Two cycloaddition strategies are described that lead to various chroman spiroketals from assorted exocyclic enol ethers. Unlike conventional thermodynamic ketalization strategies, the stereochemical outcome for this approach is determined by a kinetic cycloaddition reaction. Thus, the stereochemical outcome reflects the olefin geometry of the starting materials along with the orientation of the associated transition state. However, the initial kinetic product can also be equilibrated by acid catalysis and reconstituted into a thermodynamic stereochemical arrangement. Thus, these strategies uniquely enable synthetic access to either the thermodynamic or kinetic conformation of the spiroketal stereocenter itself. Applications of these strategies in the syntheses of berkelic acid, β-rubromycin, and paecilospirone are presented along with the use of a chroman spiroketal for the construction of heliespirones A and C.

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.

Stereodivergent total syntheses of ent-heliespirone A and C were both completed in 11 vessels and ∼24% combined overall yield (A + C). These syntheses employed an identical inverse demand Diels-Alder reaction between a surrogate for an extendedly conjugated γ-δ unsaturated ortho-quinone methide and L-lactic-acid-derived exocyclic enol ether. Novel reactions of special note include a diastereoselective reduction of a chroman spiroketal by combination of borontrifluoride etherate and triethyl silane, along with oxidative rupture of a chroman etherial ring into the corresponding p-quinone by argentic oxide (AgO). In addition, an unusual intramolecular etherification of a 3° alcohol caused by cerium ammonium nitrate was observed.

This account details the synthesis of two scyphostatin analogues exhibiting a reactive polar epoxycyclohexenone core and various amide side chains outfitted for late-stage chemical derivatization into the desirable lipophilic tails. Our efforts highlight a key ipso-dearomatization process and provide new insights regarding the incompatibility and orthogonal reactivity of scyphostatin's functional groups. We further showcase the utility of resorcinol derived 2,5-cyclohexadienones as synthetic platforms capable of participating in selective chemical reactivity, and we further demonstrate their potential for rapid elaboration into complex structural motifs.

Efficient syntheses of α-cedrene (1), α-pipitzol (2), and sec-cedrenol (3) were carried out using a new method, which was inspired by the proposed biosynthesis of the tricyclic skeleton of cedrol (12). The key transformation begins with the oxidative dearomatization of curcuphenol (5a) followed by an intramolecular [5 + 2] cycloaddition of the respective phenoxonium intermediate across the tethered olefin. The benzylic stereocenter effectively guides the formation of the first two stereocenters during the [5 + 2] reaction. The cascade then terminates with the selective incorporation of acetic acid to generate a third stereocenter, setting it apart from other previous cationic [5 + 2] reactions. The phenolic precursors (5a-h) are constructed from readily available salicylaldehydes, either as the racemate (one pot) or as a specific enantiomer (four pots) by a modification to our method for the generation of ortho-quinone methides (o-QMs).

The oxidative dearomatization of resorcinol derivatives, which are outfitted with a lactic acid derived chiral tether, and mitigated by hypervalent iodine derivatives of PhIO, affords stable chiral cyclohexadienones as useful building blocks for the construction of many highly functionalized chiral six and seven-membered ring systems. Herein, we report a multitude of remarkable and unexpected diastereoselective transformations stemming from these cyclohexadienone adducts.

A two-pot tactic is presented to reach the oxidized 2,2-dimethyl-substituted pentalene and indene ring systems.

The first total synthesis of malvone A (1) is presented in seven steps along with a nine-step formal synthesis of boryquinone (2) and an eleven-step formal synthesis of hybocarpone (3). The overall strategy, which accesses compounds 7-12 for the first time, employs an easily constructed a-tetralone, and it has significant im- plications for synthesis of the naphthoquinone portion of b-rubro- mycin (4) as well as a host of other unsymmetrical and differentially protected naphthoquinones.

Chemoselective additions of organometallic reagents to 3-benzyloxy-1,2-o-quinone are described. Various nucleophiles are shown to undergo selective 1,2-addition, 1,4-addition, and etherification. Selective 1,2-additions provide stable, nondimerizing o-quinols as a novel alternative to oxidative dearomatization.

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 beta-rubromycin and related naphthoquinone spiroketals. Several compounds were found to inhibit DNA-polymerase and telomerase in a manner resembling alpha-rubromycin and beta-rubromycin.

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 m...

We report the synthesis of diinsininone (33), the aglycone of (±)-diinsinin (2). Thereby, we complete the first construction of a proanthocyanidin (PA) type-A compound incorporating a [3.3.1]-bicyclic ketal as its characteristic core. Our strategy utilizes a coupling between a benzopyrilium salt and a flavanone that proves applicable to other PA type-A compounds. During this undertaking, treatment of naringenin (9) with 2-iodoxybenzoic acid (IBX) followed by reductive work-up affords eriodictyol (10). This reactivity mirrors that of catechol hydroxylase (F3H) found in the flavonoid pathway. Other interesting transformations include the formation of flavonoids through an ortho-quinone methide (o-QM) cycloaddition-oxidation sequence and regioselective β-glycosidations of several unprotected flavanones suggesting a likely synthesis of 2 from the aglycone 33.

Unusual reactions between various electron-rich oxazoles and ortho-quinone methides is described. This combination leads to some interesting adducts.

The oxidative dearomatization of resorcinol derivatives with various oxidants is examined, as is the reactivity of cyclohexa-2,5-dienone that emerged. The results of these studies are presented herein.

The title process proceeds with good to excellent syn selectivity to provide the corresponding aldol products.

F11334A 1 , F11334A 2 , F11334A 3 , and their corresponding resorcinol analogs were synthesized along with F11334B 1 , and F11263. In the course of these synthetic studies, several conditions for manipulating (2,3-propanediol) and (2,3-epoxypropyl) o -substituted phenols were developed as well as a variety of conditions for cleavage of aryl O- t -butyl carbonates. From enzyme assays it appears that the hydroquinone nucleus is the essential structural necessary for N-SMase inhibition. Furthermore, it appears that this family of compounds is comprised of irreversible inhibitors.

A new process for ortho-prenylation of phenols is presented within the context of known methods. All of the processes are briefly assessed with regards to the substitution patterns and accompanying functional groups tolerated by each strategy. The conclusion reached is that a new procedure using ortho-quinone methides, for which an experimental protocol is provided, offers the greatest generality and flexibility in the preparation of ortho-prenylated phenol derivatives.

A low-temperature method for generating o-quinone methides is described which permits facile introduction of assorted R substituents onto the aryl ring system at low temperature. The method is useful for the efficient preparation of ortho-ring-alkylated phenols.

A novel route to epoxysorbicillinol as well as dimers of sorbicillin is reported. The synthesis is-in principle-amenable to enantioselectivity. The key step is an oxidative dearomatization to produce a stable and highly malleable p-quinol intermediate, which undergoes a highly diastereoselective epoxidation.

Tricycloillicinone (1) and bicycloillicinone asaronacetal (2) were both isolated from extracts of the wood of Illicium tashiroi. These compounds were found to enhance the action of choline acetyltransferase, which catalyzes the synthesis of acetylcholine from its precursor. Since one of the characteristic symptoms of Alzheimer's disease involves degeneration of cholinergic neurons, resulting in markedly reduced levels of acetylcholine, compounds with the properties of 1 or 2 could well serve as agents in the treatment of such disorders. In this paper, we report the total synthesis of 1 and the construction of the core structure 3 of 2. The tricycloillicinone synthesis employed a novel strategy to control the regiochemistry of two ortho Claisen rearrangements. A sulfonyl group introduced at C2 of an allyl group effectively suppressed its unwanted rearrangement to the para position (23 → 24). Subsequently, ortho Claisen rearrangement was conducted using a reverse O-prenylated derivative 31 to furnish the de...

The total synthesis of the title compound (1), starting with (R)-(−)-α-phellandrene (6), has been accomplished. The synthesis rigorously proves the relative stereochemical relationship of the diterpenoid and carbohydrate domains of eleutherobin. Key reactions included a Nozaki−Kishi ring closure to produce a furanophane (see 37 → 38), a pyranose to furanose transposition (see 50 → 47), and a novel oxycarbaglycosidation (cf. 58 → 87) for joining the two domains.

An "sp2 -sp3 Stille coupling" of the vinyl triflate 1 and the stannyl compound 2 is a key step toward the completion of the total synthesis of eleutherobin, a natural product exhibiting taxol-like cytotoxic activity.

[reaction: see text] A strategy for the construction of electron deficient 5,6-aryloxy spiroketal is reported. The process should prove useful for the synthesis of natural products containing similar spiroketals. The strategy uncovers an unexpected rearrangement between ortho and para quinone spiroketals.

The oxidative dearomatization of resorcinol derivatives, which are outfitted with a lactic acid derived chiral tether, and mitigated by hypervalent iodine derivatives of PhIO, affords stable chiral cyclohexadienones as useful building blocks for the construction of many highly functionalized chiral six and seven-membered ring systems. Herein, we report a multitude of remarkable and unexpected diastereoselective transformations stemming from these cyclohexadienone adducts.

The first examples of enantioselective [4+2] cycloadditions of o-quinone methides (o-QMs) are reported. Their cycloaddition with trans-2-phenyl-1-cyclohexanol derived vinyl ether produces chiral benzopyrans. This procedure offers access to chiral aliphatic benzylic carbons and is applied to the synthesis of (+)-R-mimosifoliol.

Two cycloaddition strategies are described that lead to various chroman spiroketals from assorted exocyclic enol ethers. Unlike conventional thermodynamic ketalization strategies, the stereochemical outcome for this approach is determined by a kinetic cycloaddition reaction. Thus, the stereochemical outcome reflects the olefin geometry of the starting materials along with the orientation of the associated transition state. However, the initial kinetic product can also be equilibrated by acid catalysis and reconstituted into a thermodynamic stereochemical arrangement. Thus, these strategies uniquely enable synthetic access to either the thermodynamic or kinetic conformation of the spiroketal stereocenter itself. Applications of these strategies in the syntheses of berkelic acid, β-rubromycin, and paecilospirone are presented along with the use of a chroman spiroketal for the construction of heliespirones A and C.

Reaction of amino acid derivatives with SmI2/ HMPA provides a general approach to optically active title compounds.

A general method to construct 3-methyl-4-O-methylated tetramic acids displaying a C-5 stereocenter is presented. The synthetic sequence employs a SmI(2)-mediated cyclization, whereby the chirality of the emerging tetramic acid core is retained from the starting chiral amino acid. Application to palau'imide is discussed.

An acid-catalyzed intramolecular [4 + 2] cycloaddition of a non-natural bisabolene is reported. The key cyclocondensation was developed to access cyclic sesquiterpenes from linear phenolic precursors by generating a reactive o-quinone methide intermediate to initiate a cascade reaction. The new method was applied to the first total synthesis of (±)-heliol.

Robert Robinson first introduced the concept of biomimetic synthesis in 1917 with a one-pot preparation of tropinone [1]. This remarkable transformation joins three reactants together capitalizing upon the reactive proclivities of polyketides. Because aromatic compounds themselves are the end point of polyketide biosynthetic sequences, which are followed by the action of a few specific tailoring decarboxylative and oxidative enzymes, it is hard to conclude that sequences commencing with dearomatization are indeed ‘biomimetic’ [2]. However, sequential reactions initiated by oxidative phenol dearomatization can often appear as ‘biomimetic’, reaching very complex molecular architectures in short order because the functionality and the stereoand regiochemical tendencies that are programmed into the polyketide intermediates are still efficacious in the corresponding phenol derivatives and in the reactions stemming from these compounds. In this chapter, we examine some of the sequential one-pot reactions initiated by oxidative dearomatization. This discussion is by no means a comprehensive treaty on this topic. However, we attempt to untangle this subject for the benefit of interested chemists by focusing on one-pot oxidative dearomatization sequences commencing from phenols that result in the formation or cleavage of three or more C–C, C–O or C–N bonds. In all of the following schemes, the intermediate formed by the initial oxidative dearomatization undergoes further chemical reactions involving the formation and breakage of two or more bonds. Thus, the examples presented are different from most rudimentary oxidative dearomatization reactions that most often result in the usual quinol and ketal adducts [3].

Total syntheses of two structures purported as (+)-heliananes were completed in six pots. Spectral comparisons, between the synthetic and natural compounds, revealed a misassignment of the eight-membered ring in the heliananes. The key step in the syntheses of the proposed structures and the confirmation of their actual structures was a diastereoselective inverse-demand Diels-Alder reaction between an optically active enol ether and an ortho-quinone methide species, which was generated in situ at low temperature by the sequential addition of methylmagnesium bromide and di-tert-butyl dicarbonate to a salicylaldehyde.

Efficient syntheses of α-cedrene (1), α-pipitzol (2), and sec-cedrenol (3) were carried out using a new method, which was inspired by the proposed biosynthesis of the tricyclic skeleton of cedrol (12). The key transformation begins with the oxidative dearomatization of curcuphenol (5a) followed by an intramolecular [5 + 2] cycloaddition of the respective phenoxonium intermediate across the tethered olefin. The benzylic stereocenter effectively guides the formation of the first two stereocenters during the [5 + 2] reaction. The cascade then terminates with the selective incorporation of acetic acid to generate a third stereocenter, setting it apart from other previous cationic [5 + 2] reactions. The phenolic precursors (5a-h) are constructed from readily available salicylaldehydes, either as the racemate (one pot) or as a specific enantiomer (four pots) by a modification to our method for the generation of ortho-quinone methides (o-QMs).

Robert Robinson first introduced the concept of biomimetic synthesis in 1917 with a one-pot preparation of tropinone [1]. This remarkable transformation joins three reactants together capitalizing upon the reactive proclivities of polyketides. Because aromatic compounds themselves are the end point of polyketide biosynthetic sequences, which are followed by the action of a few specific tailoring decarboxylative and oxidative enzymes, it is hard to conclude that sequences commencing with dearomatization are indeed ‘biomimetic’ [2]. However, sequential reactions initiated by oxidative phenol dearomatization can often appear as ‘biomimetic’, reaching very complex molecular architectures in short order because the functionality and the stereoand regiochemical tendencies that are programmed into the polyketide intermediates are still efficacious in the corresponding phenol derivatives and in the reactions stemming from these compounds. In this chapter, we examine some of the sequential one-pot reactions initiated by oxidative dearomatization. This discussion is by no means a comprehensive treaty on this topic. However, we attempt to untangle this subject for the benefit of interested chemists by focusing on one-pot oxidative dearomatization sequences commencing from phenols that result in the formation or cleavage of three or more C–C, C–O or C–N bonds. In all of the following schemes, the intermediate formed by the initial oxidative dearomatization undergoes further chemical reactions involving the formation and breakage of two or more bonds. Thus, the examples presented are different from most rudimentary oxidative dearomatization reactions that most often result in the usual quinol and ketal adducts [3].

A formal synthesis of berkelic acid is reported. The strategy employs the combination of a chiral exocyclic enol ether and an achiral isochromanone to afford the chroman spiroketal core via a base-triggered generation and cycloaddition of an o-quinone methide intermediate. Other key steps include equilibration of the spiroketal, intramolecular benzylic oxidation, and lactone addition/hemiketal reduction; all occur with good diastereoselectivity.

The furan derivative (1) undergoes diastereoselective Diels-Alder reac- tions with dienophilic species such as α,β-unsaturated esters, nitriles, sulfones, and imides in good to excellent chemical yields. The oxobi- cyclic adducts obtained are amenable to chemical transformations which render them useful to natural product synthesis

A ring expansion/ring contraction sequence is one of the key steps in the stereoselective synthesis of the tricyclic eleutheside skeleton 2 from α-phellandrene 1. Eleuthesides are natural products that are isolated from different marine sources, and several of these compounds display taxol-like anticancer activity.