Development of a catalytic enantioselective synthesis of the guanacastepene and heptemerone tricyclic core.

For nearly two decades, synthetic chemists have been fascinated by the structural complexity and synthetic challenges afforded by the guanacastepene and heptemerone diterpenoids.Numerous synthetic approaches to these compounds have been reported, but to date the application of enantioselective catalysis to this problem has not been realized. Herein we report an enantioselective synthesis of an advanced intermediate corresponding to the tricyclic core common to the guanacastepenes and heptemerones. Highlights of this work include sequential Pd-catalyzed decarboxylative allylic alkylation reactions to generate the two all carbon quaternary stereocenters, the use of ring-closing metathesis to close the A ring in the presence of a distal allyl sidechain, and a region and diastereoselective oxidation of an trienol ether to introduce oxygenation on the A ring.

Concerning the mechanism of iodine(iii)-mediated oxidative dearomatization of phenols.

The iodine(iii)-mediated oxidative dearomatization of phenols has proven to be a general method for the preparation of cyclohexadienones. While this is a widely used reaction, there is still a great deal of uncertainty regarding the mechanistic pathway followed by these reactions. In part, this is due to the highly unstable nature of many of the key intermediates, which makes their direct detection extremely difficult. In order to gain some insight into these mechanistic questions, DFT calculations [M06-2X/6-31+G(d) for C, H, and O and LANL2DZdp for iodine] were used to evaluate the two most commonly proposed reaction mechanisms. These results show that unimolecular fragmentation of an oxygen-bound intermediate to give a phenoxenium ion (TS1) is preferred over direct addition of the nucleophile to the aromatic ring of the activated phenol (TS3). In addition, results are presented that suggest protonation and/or hydrogen bonding may play a key role in lowering the energy of the unimolecular fragmentation pathway.

Experimental evidence for the formation of cationic intermediates during iodine(iii)-mediated oxidative dearomatization of phenols.

Iodine(iii)-based oxidants are commonly used reagents for the oxidative dearomatization of phenols. Having a better understanding of the mechanism through which these reactions proceed is important for designing new iodine(iii)-based reagents, catalysts, and reactions. We have performed a Hammett analysis of the oxidative dearomatization of substituted 4-phenylphenols. This study confirms that iodine(iii)-mediated oxidative dearomatizations likely proceed through cationic phenoxenium ions and not the direct addition of a nucleophile to an iodine-bound phenol intermediate.

Stereoselective synthesis of the C14-C23 fragment of biselyngbyolide A and B enabled by transition metal catalysis.

Transition met al catalysis has enabled the highly stereoselective and protecting group-free synthesis of the C14-C23 fragment of the apoptosis-inducing natural products biselyngbyolide A and B. A Pd-catalyzed Stille reaction between a vinyl stannane and a crotyl carbonate formed the skipped diene with complete control of the the trisubstituted bond and excellent control over the branched/linear products. A Cu-catalyzed Stahl oxidation was used to form the requisite aldehyde needed for a Ag-catalyzed asymmetric allylation. The latter provided the final fragment with excellent stereochemical control.

Torsional steering as friend and foe: development of a synthetic route to the briarane diterpenoid stereotetrad.

Two synthetic routes to the briarane stereotetrad have been investigated. The first route employed a boron aldol reaction to establish the stereogenic all-carbon quaternary carbon (C1). In this case, it was found that torsional steering in the transition state led to the formation of the undesired configuration at this position. The second route makes use of a highly diastereoselective acetylide conjugate addition/ß-ketoester alkylation sequence to construct the vicinal C1 and C10 stereocenters with the correct relative configuration. Originally, it was proposed that torsional steering in the transition state for the ketoester alkylation step was the primary factor responsible for generating the major product. DFT calculations reveal that while torsional steering does play a role, larger conformational factors must also be considered. These calculations also reveal that an unusual C-Hπ(alkyne) interaction may contribute to lowering the energy of one transition state that leads to the observed stereoisomer. Ultimately, this strategy leads to a concise synthesis (under 10 steps) of the stereotetrad core common to the briarane diterpenoids.

Asymmetric transformations of achiral 2,5-cyclohexadienones.

Cyclohexadienones are versatile platforms for performing asymmetric synthesis as evidenced by the numerous natural product syntheses that exploit their diverse reactivity profile. However, there are few general methods available for the direct asymmetric synthesis of chiral cyclohexadienones. To circumvent this problem, several researchers have developed catalytic asymmetric methods that employ readily available achiral 2,5-cyclohexadienones as substrates. Many of these reactions are desymmetrizations in which one of the enantiotopic alkenes of an achiral dienone is transformed. Others involve selective reaction at one alkene of an unsymmetrically substituted, achiral dienone. This review will cover advances in this area over the last 20 years and the application of these strategies in complex molecule synthesis.

Asymmetric oxidative dearomatizations promoted by hypervalent iodine(III) reagents: an opportunity for rational catalyst design?

The use of and λ3- and λ5-iodanes in the oxidative dearomatization of phenols is a well-established and general procedure for the construction of cyclohexadienone structures. However, their use in asymmetric dearomatization reactions is quite underdeveloped and, despite work by several research groups over the past several years, a general chiral aryl iodide catalyst has yet to emerge. This article will serve to highlight the significant progress that has been made in this area and will reveal some of deficiencies in the literature that the author believes may be hindering further progress.

Origin of stereoselectivity of the alkylation of cyclohexadienone-derived bicyclic malonates.

The diastereoselectivity of the alkylation of bicyclic malonates has been studied experimentally and computationally. In accordance with previous observations during a total synthesis of sorbicillactone A, alkylations involving methyl iodide proceed from the concave (endo) face of the bicyclo[4.3.0]nonene ring system. In contrast, carbon-based electrophiles larger than methyl iodide approach from the convex (exo) face. Computational studies using M06-2X and B3LYP methods have revealed that the observed stereoselectivity is explained by subtle energetic differences between a staggered transition state with less torsional strain and unfavorable steric interactions with the cyclohexenone ring. Using this model as a guide, hydrogenation of the C-C double bond was used to alter the steric environment of the substrate. As expected, this led to a reversal in the diastereoselectivity during the alkylation with methyl iodide.

Ligand and substrate effects during Pd-catalyzed cyclizations of alkyne-tethered cyclohexadienones.

The effects of ligand and substrate choice on the Pd-catalyzed cyclization of alkyne-tethered cyclohexadienones were examined. In the presence of a chiral ligand, the enantioselectivity of the desymmetrization is remarkably sensitive to structural changes in both the ligand and the substrate. Additionally, the regioselectivity of the reaction (5- vs. 6-membered ring formation) is dependent on the proximity of heteroatoms to the alkyne.

Synthesis of enantioenriched γ-quaternary cycloheptenones using a combined allylic alkylation/Stork-Danheiser approach: preparation of mono-, bi-, and tricyclic systems.

A general method for the synthesis of ß-substituted and unsubstituted cycloheptenones bearing enantioenriched all-carbon γ-quaternary stereocenters is reported. Hydride or organometallic addition to a seven-membered ring vinylogous ester followed by finely tuned quenching parameters achieves elimination to the corresponding cycloheptenone. The resulting enones are elaborated to bi- and tricyclic compounds with potential for the preparation of non-natural analogs and whose structures are embedded in a number of cycloheptanoid natural products.

The sorbicillinoid family of natural products: isolation, biosynthesis, and synthetic studies.

The sorbicillinoids are a family of hexaketide metabolites that have been isolated from a variety of fungal sources, collected from both marine and terrestrial sources. Since 1948, the family has grown in size to include over 50 members, many of which have complex, highly oxygenated, bicyclic and tricyclic frameworks. In conjunction with their biological activity, the structural complexity of these structures has inspired several synthetic campaigns and has also led to controversy surrounding the biosynthetic pathway responsible for the natural production of these compounds. Through this review, we aim to give a historical perspective to each of these areas and hope to inspire new avenues of research for addressing the knowledge gaps that still exist.

Enantioselective decarboxylative alkylation reactions: catalyst development, substrate scope, and mechanistic studies.

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic ß-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

Regioselective and stereoselective cyclizations of cyclohexadienones tethered to active methylene groups.

The cyclization of 2,5-cyclohexadienones tethered to activated methylene groups was studied. The substitution around the cyclohexadienone ring serves to regioselectively direct these cyclizations based primarily on electronic effects. In the case of brominated substrates, these reactions proceed to give highly unusual electron-deficient tricyclic cyclopropanes. By using a Cinchona alkaloid-based phase-transfer catalyst, prochiral cyclohexadienones can be desymmetrized with moderate stereoselectivity.

Palladium-Catalyzed Asymmetric Alkylation in the Synthesis of Cyclopentanoid and Cycloheptanoid Core Structures Bearing All-Carbon Quaternary Stereocenters.

General catalytic asymmetric routes toward cyclopentanoid and cycloheptanoid core structures embedded in numerous natural products have been developed. The central stereoselective transformation in our divergent strategies is the enantioselective decarboxylative alkylation of seven-membered ß-ketoesters to form α-quaternary vinylogous esters. Recognition of the unusual reactivity of ß-hydroxyketones resulting from the addition of hydride or organometallic reagents enabled divergent access to γ-quaternary acylcyclopentenes through a ring contraction pathway or γ-quaternary cycloheptenones through a carbonyl transposition pathway. Synthetic applications of these compounds were explored through the preparation of mono-, bi-, and tricyclic derivatives that can serve as valuable intermediates for the total synthesis of complex natural products. This work complements our previous work with cyclohexanoid systems.

Rapid, enantioselective synthesis of the C1-C13 fragment of biselyngbyolide B.

A rapid synthesis of the C1-C13 fragment of biselynbyolide A and B is reported. The judicious use of catalytic transformations for C-C bond formation and stereocenter generation greatly minimizes the use of protecting groups and oxidation state changes, as compared to previously reported routes to similar fragments.

Synthetic explorations of the briarane jungle: progress in developing a synthetic route to a common family of diterpenoid natural products.

The briarane diterpenoids are a large family of marine natural products that have been primarily isolated from gorgonian octocorals around the world. Structurally, the family is characterized by a trans-fused bicyclo[8.4.0]tetradecane ring system containing a central, stereogenic, all-carbon quaternary carbon (C1) flanked by three additional stereocentres (C2, C10, C14). Many family members have demonstrated biological activity in numerous areas, including: cytotoxicity, anti-inflammatory, antiviral, antifungal, immunomodulatory and insect control. Despite their interesting structural properties and bioactivity, the briaranes have been largely overlooked by the synthetic community. However, in recent years, several research groups have reported progress toward developing a synthetic route to these natural products. Most of these efforts have focused on the stereoselective construction of the central C1-C2-C10-C14 stereotetrad. This review will discuss the various synthetic efforts aimed at the briarane diterpenoids along with the challenges that remain.

New Strategy To Access Enantioenriched Cyclohexadienones: Kinetic Resolution of para-Quinols by Organocatalytic Thiol-Michael Addition Reactions.

Existing stereoselective routes to 2,5-cyclohexadienones involve either desymmetrization of an achiral substrate or have attempted to perform an asymmetric dearomatization of a phenol. Herein, we report proof-of-principle experiments aimed at developing a kinetic resolution as an alternative method for accessing enantioenriched 2,5-cyclohexadienones. More specifically, chiral bifunctional thiourea catalysts were used to promote the addition of 2-thionapthalene into unsymmetric para-quinols. The selectivity of the kinetic resolution was found to be quite sensitive to substitution around the substrate.

α-Alkylation of a norbornene-derived tricyclic ketone: are steric factors really in control?

Density functional theory (DFT) has been used to investigate the α-alkylation of a chiral tricyclic ketone. These calculations reveal that torsional strain and a strong conformational preference, rather than steric influences, are responsible for the high levels of observed stereoselectivity and suggest a way by which alternative stereoisomers could be accessed.

A concise synthetic route to the stereotetrad core of the briarane diterpenoids.

A concise synthesis (under 10 steps) of the stereotetrad core of the briarane diterpenoids is reported. This approach harnesses the unique reactivity of salicylate ester derived 2,5-cyclohexadienones to quickly build complexity. In particular, a highly diastereoselective acetylide conjugate addition/ß-ketoester alkylation sequence was used to set the relative configuration of the C1 (quaternary) and C10 (tertiary) vicinal stereocenters. The sterochemical outcome of the ß-ketoester alkylation appears to be governed by torsional steering in the transition state.