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 regio- and diastereoselective oxidation of a trienol ether to introduce oxygenation on the A ring

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 β-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

Ring-Contraction Strategy for the Practical, Scalable, Catalytic Asymmetric Synthesis of Versatile γ-Quaternary Acylcyclopentenes

Contraction action! A simple protocol for the catalytic asymmetric synthesis of highly functionalized γ-quaternary acylcyclopentenes (see schematic) in up to 91 % overall yield and 92 % ee has been developed. The reaction sequence employs a palladium-catalyzed enantioselective alkylation reaction and exploits the unusual stability of β-hydroxy cycloheptanones to achieve a general and robust method for performing two-carbon ring contractions

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones

The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF_3)_3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee’s up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee

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 β-ketoesters to form α-quaternary vinylogous esters. Recognition of the unusual reactivity of β-hydroxyketones resulting from the addition of hydride or organometallic reagents enabled divergent access to y-quaternary acylcyclopentenes through a ring contraction pathway or y-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

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 β-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

Comprehensive, Evidence-Based, Consensus Guidelines for Prescription of Opioids for Chronic Non-Cancer Pain from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. OBJECTIVES: In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. METHODS: The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed. The multidisciplinary panel finalized 20 guideline recommendations for prescription of opioids for chronic non-cancer pain. Summary of the results showed over 90% agreement for the final 20 recommendations with strong consensus. The consensus guidelines included 4 sections specific to opioid therapy with 1) ten recommendations particular to initial steps of opioid therapy; 2) five recommendations for assessment of effectiveness of opioid therapy; 3) three recommendations regarding monitoring adherence and side effects; and 4) two general, final phase recommendations. LIMITATIONS: There is a continued paucity of literature of long-term opioid therapy addressing chronic non-cancer pain. Further, significant biases exist in the preparation of guidelines, which has led to highly variable rules and regulations across various states. CONCLUSION: These guidelines were developed based upon a comprehensive review of the literature, consensus among expert panelists, and in alignment with patient preferences, and shared decision-making so as to improve the long-term pain relief and function in patients with chronic non-cancer pain. Consequently, it was concluded - and herein recommended - that chronic opioid therapy should be provided in low doses with appropriate adherence monitoring and understanding of adverse events only to those patients with a proven medical necessity, and who exhibit stable improvement in both pain relief and activities of daily function, either independently or in conjunction with other modalities of treatments

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/β-ketoester alkylation sequence was used to set the relative configuration of the C1 (quaternary) and C10 (tertiary) vicinal stereocenters. The sterochemical outcome of the β-ketoester alkylation appears to be governed by torsional steering in the transition state

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

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