15NRORC: An Azine Labeling Protocol.

A practical method for the synthesis of 15N-labeled azines with a high degree of isotopic enrichment is described. Activation of azine heterocycles with an electron-deficient arene allows for the facile substitution of the nitrogen atom with a specifically designed 15N-labeled reagent that undergoes a canonical ANRORC-type mechanism. A wide range of azines can be converted to their corresponding 15N isotopologs using this method, and it also allows for dearomative access to reduced heterocyclic congeners. A short dearomative formal synthesis of 15N-solifenacin is accomplished as well to demonstrate a practical application of this method for generating labeled pharmaceuticals.

Dearomative Access to (-)-Thebaine and Derivatives.

A synthesis of the natural product thebaine is reported in eight steps from commercially available starting materials, hinging on the dearomatization and coupling of simple aromatic starting materials. This provides divergent access to two unnatural opioid derivatives and is aimed at the long-term development of synthetic opioid analogs of the "wonderdrug" Naloxone. Additionally, a formal enantioselective synthesis of all reported targets is disclosed that leverages a catalytic asymmetric dearomatization via anion-pairing catalysis.

Six-Step Synthesis of (±)-Lysergic Acid.

This article describes a concise synthesis of lysergic acid from simple aromatic precursors. The successful strategy relies on the coupling, dearomatization, and cyclization of a halopyridine with a 4-haloindole derivative in 6 total synthetic steps from commercial starting materials. In addition to highlighting the advantages of employing dearomative retrosynthetic analysis, the design is practical and anticipated to enable the synthesis of novel neuroactive compounds as exemplified by the synthesis of a novel natural product derivative, 12-chlorolysergic acid.

Revisiting the manzamine biosynthetic hypothesis.

Covering: up to 2023The marine environment represents a rich yet challenging source of novel therapeutics. These challenges are best exemplified by the manzamine class of alkaloids, featuring potent bioactivities, difficult procurement, and a biosynthetic pathway that has eluded characterization for over three decades. This review highlights postulated biogenic pathways toward the manzamines, evaluated in terms of current biosynthetic knowledge and metabolic precedent.

Regiodivergent Asymmetric Pyridinium Additions: Mechanistic Insight and Synthetic Applications.

A practical protocol for the first regiodivergent asymmetric addition of aryl and alkenyl organometallic reagents to substituted N-alkyl pyridinium heterocycles is described. The couplings proceed with high regiochemical and stereochemical selectivities, and provide access to chiral 1,2,3- and 1,3,4-trisubstituted dihydropyridine products, controlled by judicious choice of nitrogen activating agent. To this end, a correlation was found between the parameterized size of the activating group and the C2/C4 regioselectivity in the couplings. The utility of the described chemistry was demonstrated in two concise asymmetric syntheses of (+)-N-methylaspidospermidine and (-)-paroxetine.

Regioselective Asymmetric Alkynylation of N-Alkyl Pyridiniums.

Disclosed in this Letter is a novel asymmetric addition of alkynyl nucleophiles to N-alkylpyridinium electrophiles. The coupling is effected under mild and simple reaction conditions, affording dihydropyridine products with complete regiochemical and stereochemical control. In addition to several manipulations of the dihydropyridine products, the utility of this transformation is demonstrated through a concise, dearomative, and asymmetric synthesis of (+)-lupinine, a natural acetylcholine esterase inhibitor.

A predictive model for additions to N-alkyl pyridiniums.

Disclosed in this communication is a thorough study on the dearomative addition of organomagnesium nucleophiles to N-alkyl pyridinium electrophiles. The regiochemical outcomes have observable and predictable trends associated with the substituent patterns on the pyridinium electrophile. Often, the substituent effects can be either additive, giving high selectivities, or ablative, giving competing outcomes. Additionally, the nature of the organometallic nucleophilic component was also investigated for its role in the regioselective outcome. The effects of either reactive component are important to both the overall reactivity and site of nucleophilic addition. The utility of these observed trends is demonstrated in a concise, dearomative synthesis of a tricyclic compound shown to have insecticidal activity.

Ortho/Ipso Alkylborylation of Aryl Iodides.

This work describes a method for the difunctionalization of aryl iodides to generate polysubstituted arenes via Pd catalysis. The reaction hinges on the unique interplay between norbornene and the metal catalyst to impart a guided ortho C-H alkylation event followed by a programmatic ipso borylation to provide a diverse array of substituted arene products. The utility of this transformation is demonstrated through the functionalization of the boronic ester to a variety of valuable functionalities.

CO2 or SO2: Should It Stay, or Should It Go?

A broad computational analysis of carbon-centered radical formation via the loss of either CO2 or SO2 from the respective RXO2 radical precursors (X = C or S) reveals dramatic differences between these two types of dissociative processes. Whereas the C-C scission with the loss of CO2 is usually exothermic, the C-S scission with the loss of SO2 is generally endothermic. However, two factors can make the C-S scissions thermodynamically favorable: increased entropy, characteristic for the dissociative processes, and stereoelectronic influences of substituents. The threshold between endergonic and exergonic C-S fragmentations depends on subtle structural effects. In particular, the degree of fluorination in a radical precursor has a notable impact on the reaction outcome. This study aims to demystify the intricacies in reactivity regarding the generation of radicals from sulfinates and carboxylates, as related to their role in radical cross-coupling.

Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery.

The modern constraints of drug discovery demand a rigorous validation process of all new reactions prior to widespread implementation. To this end, sulfinates (now marketed as Diversinates) have seen alacritous adoption by the medicinal chemistry community, as evidenced by the recent outpour of both patent and primary reports. Featuring more than 50 examples, this review seeks to highlight those particularly compelling cases published in the past 5 years, with an eye toward the identification of robust and predictable trends in reactivity.

Radical Retrosynthesis.

In The Logic of Chemical Synthesis, E. J. Corey stated that the key to retrosynthetic analysis was a "wise choice of appropriate simplifying transforms" ( Corey , E. J. ; Cheng , X.-M. The Logic of Chemical Synthesis ; John Wiley : New York , 1989 ). Through the lens of "ideality", chemists can identify opportunities that can lead to more practical, scalable, and sustainable synthesis. The percent ideality of a synthesis is defined as [(no. of construction rxns) + (no. of strategic redox rxns)]/(total no. of steps) × 100. A direct consequence of designing "wise" or "ideal" plans is that new transformations often need invention. For example, if functional group interconversions are to be avoided, one is faced with the prospect of directly functionalizing C-H bonds ( Gutekunst , W. R. ; Baran , P. S. Chem. Soc. Rev. 2011 , 40 , 1976 ; Brückl , T. ; et al. Acc. Chem. Res. 2012 , 45 , 826 ). If protecting groups are minimized, methods testing the limits of chemoselectivity require invention ( Baran , P. S. ; et al. Nature 2007 , 446 , 404 ; Young , I. S. ; Baran , P. S. Nat. Chem. 2009 , 1 , 193 ). Finally, if extraneous redox manipulations are to be eliminated, methods directly generating key skeletal bonds result ( Burns , N. Z. ; et al. Angew. Chem., Int. Ed. 2009 , 48 , 2854 ). Such analyses applied to total synthesis have seen an explosion of interest in recent years. Thus, it is the interplay of aspirational strategic demands with the limits of available methods that can influence and inspire ingenuity. E. J. Corey's sage advice holds true when endeavoring in complex molecule synthesis, but together with the tenets of the "ideal" synthesis, avoiding concession steps leads to the most strategically and tactically optimal route ( Hendrickson , J. B. J. Am. Chem. Soc. 1975 , 97 , 5784 ; Gaich , T. ; Baran , P. S. J. Org. Chem. 2010 , 75 , 4657 ). Polar disconnections are intuitive and underlie much of retrosynthetic logic. Undergraduates exposed to multistep synthesis are often taught to assemble organic molecules through the combination of positively and negatively charged synthons because, after all, opposites attract. Indeed, the most employed two-electron C-C bond forming reactions today are those based upon either classical cross-coupling reactions (e.g., Suzuki, Negishi, or Heck) or polar additions (aldol, Michael, or Grignard). These reactions are the mainstay of modern synthesis and have revolutionized the way molecules are constructed due to their robust and predictable nature. In contrast, radical chemistry is sparsely covered beyond the basic principles of radical chain processes (i.e., radical halogenation). The historical perception of radicals as somewhat uncontrollable species does not help the situation. As a result, synthetic chemists are not prone to make radical-based strategic bond disconnections during first-pass retrosynthetic analyses. Recent interest in the use of one-electron radical cross-coupling (RCC) methods has been fueled by the realization of their uniquely chemoselective profiles and the opportunities they uncover for dramatically simplifying synthesis. In general, such couplings can proceed by relying on the innate preferences of a substrate (innate RCC) or through interception with a mediator (usually a transition metal) to achieve programmed RCC. This Account presents a series of case studies illustrating the inherent strategic and tactical advantages of employing both types of radical-based cross-couplings in a variety of disparate settings. Thematically, it is clear that one-electron disconnections, while not considered to be intuitive, can serve to enable syntheses that are more direct and feature a minimal use of protecting group chemistry, functional group interconversions, and nonstrategic redox fluctuations.

Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies.

The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (-)-2( S)-cathafoline, (+)-akuammiline, and (-)-Ψ-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection-cyclization cascade. The total syntheses of (-)-Ψ-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+)-strictamine and (+)-akuammiline to ultimately provide (-)-10-demethoxyvincorine and a new analogue thereof.

Decarboxylative Alkynylation.

The development of a new decarboxylative cross-coupling method that affords terminal and substituted alkynes from various carboxylic acids is described using both nickel- and iron-based catalysts. The use of N-hydroxytetrachlorophthalimide (TCNHPI) esters is crucial to the success of the transformation, and the reaction is amenable to in situ carboxylic acid activation. Additionally, an inexpensive, commercially available alkyne source is employed in this formal homologation process that serves as a surrogate for other well-established alkyne syntheses. The reaction is operationally simple and broad in scope while providing succinct and scalable avenues to previously reported synthetic intermediates.

Scalable Synthesis of (-)-Thapsigargin.

Total syntheses of the complex, highly oxygenated sesquiterpenes thapsigargin (1) and nortrilobolide (2) are presented. Access to analogues of these promising bioactive natural products has been limited to tedious isolation and semisynthetic efforts. Elegant prior total syntheses demonstrated the feasibility of creating these entitites in 36-42 step processes. The currently reported route proceeds in a scalable and more concise fashion by utilizing two-phase terpene synthesis logic. Salient features of the work include application of the classic photosantonin rearrangement and precisely choreographed installation of the multiple oxygenations present on the guaianolide skeleton.

Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (-)-2(S)-Cathafoline, and (-)-Aspidophylline A.

The akuammiline alkaloids are a family of natural products that have been widely studied for decades. Although notable synthetic achievements have been made recently, akuammilines that possess a methanoquinolizidine core have evaded synthetic efforts. We report an asymmetric approach to these alkaloids, which has culminated in the first total syntheses of (-)-2(S)-cathafoline and the long-standing target (+)-strictamine. Moreover, the first enantioselective total synthesis of aspidophylline A is described.

Fischer Indolizations as a Strategic Platform for the Total Synthesis of Picrinine.

Picrinine, which is a member of the akuammiline family of alkaloids, was first isolated in 1965 from the leaves of Alstonia scholaris. The natural product possesses a daunting polycyclic skeleton that contains a furanoindoline, a bridged [3.3.1]azabicycle, two N,O-acetal linkages, and six stereogenic centers. These structural features render picrinine a challenging and attractive target for total synthesis. This paper provides a full account of our synthetic forays toward picrinine, which culminates in the first total synthesis of this long-standing target. Central to the success of our approach is the use of the Fischer indolization reaction to introduce the C7 quaternary stereocenter and the indoline nucleus of the natural product's scaffold. We probe some of the subtleties of this classic transformation by examining some of the most complex Fischer indolization substrates to date. Additionally, we describe various roadblocks encountered in our experimental efforts, which were successfully overcome to complete the total synthesis of picrinine.

Cascade reactions: a driving force in akuammiline alkaloid total synthesis.

The akuammiline alkaloids are a family of intricate natural products which have received considerable attention from scientists worldwide. Despite the fact that many members of this alkaloid class were discovered over 50 years ago, synthetic chemistry has been unable to address their architectures until recently. This minireview provides a brief overview of the rich history of the akuammiline alkaloids, including their isolation, structural features, biological activity, and proposed biosyntheses. Furthermore, several recently completed total syntheses are discussed in detail. These examples not only serve to highlight modern achievements in alkaloid total synthesis, but also demonstrate how the molecular scaffolds of the akuammilines have provided inspiration for the discovery and implementation of innovative cascade reactions for the rapid assembly of complex structures.

Total synthesis of the akuammiline alkaloid picrinine.

We report the first total synthesis of the complex akuammiline alkaloid picrinine, which was first isolated nearly five decades ago. Our synthetic approach features a concise assembly of the [3.3.1]-azabicyclic core, a key Fischer indolization reaction to forge the natural product's carbon framework, and a series of delicate late-stage transformations to complete the synthesis. Our synthesis of picrinine also constitutes a formal synthesis of the related polycyclic alkaloid strictamine.