The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using ...prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.
Phorbol, the flagship member of the tigliane diterpene family, has been known for over 80 years and has attracted attention from many chemists and biologists owing to its intriguing chemical ...structure and the medicinal potential of phorbol esters. Access to useful quantities of phorbol and related analogues has relied on isolation from natural sources and semisynthesis. Despite efforts spanning 40 years, chemical synthesis has been unable to compete with these strategies, owing to its complexity and unusual placement of oxygen atoms. Purely synthetic enantiopure phorbol has remained elusive, and biological synthesis has not led to even the simplest members of this terpene family. Recently, the chemical syntheses of eudesmanes, germacrenes, taxanes and ingenanes have all benefited from a strategy inspired by the logic of two-phase terpene biosynthesis in which powerful C-C bond constructions and C-H bond oxidations go hand in hand. Here we implement a two-phase terpene synthesis strategy to achieve enantiospecific total synthesis of (+)-phorbol in only 19 steps from the abundant monoterpene (+)-3-carene. The purpose of this synthesis route is not to displace isolation or semisynthesis as a means of generating the natural product per se, but rather to enable access to analogues containing unique placements of oxygen atoms that are otherwise inaccessible.
Along with amide bond formation, Suzuki cross‐coupling, and reductive amination, the Buchwald–Hartwig–Ullmann‐type amination of aryl halides stands as one of the most employed reactions in modern ...medicinal chemistry. The work herein demonstrates the potential of utilizing electrochemistry to provide a complementary avenue to access such critical bonds using an inexpensive nickel catalyst under mild reaction conditions. Of note is the scalability, functional‐group tolerance, rapid rate, and the ability to employ a variety of aryl donors (Ar−Cl, Ar−Br, Ar−I, Ar−OTf), amine types (primary and secondary), and even alternative X−H donors (alcohols and amides).
Amination electrified: Arguably one of the most important types of bonds, the C−N bond, can now be forged under nickel‐catalysis with the aid of electrochemistry. Broad scope, scalability, sustainability, mildness, and rapid reacion rates are some highlights of this interesting new reaction. Tf=trifluoromethanesulfonyl.
Radical Retrosynthesis Smith, Joel M; Harwood, Stephen J; Baran, Phil S
Accounts of chemical research,
08/2018, Letnik:
51, Številka:
8
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Conspectus 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.
A new transformation is presented that enables chemists to couple simple alkyl carboxylic acids with aryl zinc reagents under Ni-catalysis. The success of this reaction hinges on the unique use of ...redox-active esters that allow one to employ such derivatives as alkyl halides surrogates. The chemistry exhibits broad substrate scope and features a high degree of practicality. The simple procedure and extremely inexpensive nature of both the substrates and pre-catalyst (NiCl2·6H2O, ca. $9.5/mol) bode well for the immediate widespread adoption of this method.
Innate and Guided C–H Functionalization Logic Brückl, Tobias; Baxter, Ryan D; Ishihara, Yoshihiro ...
Accounts of chemical research,
06/2012, Letnik:
45, Številka:
6
Journal Article
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The combustion of organic matter is perhaps the oldest and most common chemical transformation utilized by mankind. The generation of a C–O bond at the expense of a C–H bond during this process may ...be considered the most basic form of C–H functionalization. This illustrates the extreme generality of the term “C–H functionalization”, because it can describe the conversion of literally any C–H bond into a C–X bond (X being anything except H). Therefore, it may be of use to distinguish between what, in our view, are two distinct categories of C–H functionalization logic: “guided” and “innate”. Guided C–H functionalizations, as the name implies, are guided by external reagents or directing groups (covalently or fleetingly bound) to install new functional groups at the expense of specifically targeted C–H bonds. Conversely, innate C–H functionalizations may be broadly defined as reactions that exchange C–H bonds for new functional groups based solely on natural reactivity patterns in the absence of other directing forces. Two substrates that illustrate this distinction are dihydrojunenol and isonicotinic acid. The C–H functionalization processes of hydroxylation or arylation, respectively, can take place at multiple locations on each molecule. Innate functionalizations lead to substitution patterns that are dictated by the inherent bias (steric or electronic) of the substrate undergoing C–H cleavage, whereas guided functionalizations lead to substitution patterns that are controlled by external directing forces such as metal complexation or steric bias of the reagent. Although the distinction between guided and innate C–H functionalizations may not always be clear in cases that do not fit neatly into a single category, it is a useful convention to consider when analyzing reactivity patterns and strategies for synthesis. We must emphasize that although a completely rigorous distinction between guided and innate C–H functionalization may not be practical, we have nonetheless found it to be a useful tool at the planning stage of synthesis. In this Account, we trace our own studies in the area of C–H functionalization in synthesis through the lens of “guided” and “innate” descriptors. We show how harnessing innate reactivity can be beneficial for achieving unique bond constructions between heterocycles and carbonyl compounds, enabling rapid and scalable total syntheses. Guided and innate functionalizations were used synergistically to create an entire family of terpenes in a controlled fashion. We continue with a discussion of the synthesis of complex alkaloids with high nitrogen content, which required the invention of a uniquely chemoselective innate C–H functionalization protocol. These findings led us to develop a series of innate C–H functionalization reactions for forging C–C bonds of interest to the largest body of practicing organic chemists: medicinal chemists. Strategic use of C–H functionalization logic can have a dramatically positive effect on the efficiency of synthesis, whether guided or innate.
Verruculogen and fumitremorgin A are bioactive alkaloids that contain a unique eight-membered endoperoxide. Although related natural products such as fumitremorgins B and C have been previously ...synthesized, we report the first synthesis of the more complex, endoperoxide-containing members of this family. A concise route to verruculogen and fumitremorgin A relied not only on a hydroperoxide/indole hemiaminal cyclization, but also on the ability to access the seemingly simple starting material, 6-methoxytryptophan. An iridium-catalyzed C–H borylation/Chan–Lam procedure guided by an N-TIPS group enabled the conversion of a tryptophan derivative into a 6-methoxytryptophan derivative, proving to be a general way to functionalize the C6 position of an N,C3-disubstituted indole for the synthesis of indole-containing natural products and pharmaceuticals.
Decarboxylative borylation Li, Chao; Wang, Jie; Barton, Lisa M. ...
Science (American Association for the Advancement of Science),
06/2017, Letnik:
356, Številka:
6342
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The widespread use of alkyl boronic acids and esters is frequently hampered by the challenges associated with their preparation. We describe a simple and practical method to rapidly access densely ...functionalized alkyl boronate esters from abundant carboxylic substituents. This broad-scope nickel-catalyzed reaction uses the same activating principle as amide bond formation to replace a carboxylic acid moiety with a boronate ester. Application to peptides allowed expedient preparations of α-amino boronic acids, often with high stereoselectivity, thereby facilitating synthesis of the alkyl boronic acid drugs Velcade and Ninlaro as well as a boronic acid version of the iconic antibiotic vancomycin. The reaction also enabled the discovery and extensive biological characterization of potent human neutrophil elastase inhibitors, which offer reversible covalent binding properties.
11-Step Total Synthesis of Teleocidins B‑1–B‑4 Nakamura, Hugh; Yasui, Kosuke; Kanda, Yuzuru ...
Journal of the American Chemical Society,
01/2019, Letnik:
141, Številka:
4
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A unified and modular approach to the teleocidin B family of natural products is presented that proceeds in 11 steps and features an array of interesting strategies and methods. Indolactam V, the ...known biosynthetic precursor to this family, was accessed through electrochemical amination, Cu-mediated aziridine opening, and a remarkable base-induced macrolactamization. Guided by a desire to minimize concession steps, the tactical combination of C–H borylation and a Sigman–Heck transform enabled the convergent, stereocontrolled synthesis of the teleocidins.
Here, we report on a scalable route to the polyhydroxylated steroid ouabagenin with an unusual take on the age-old practice of steroid semisynthesis. The incorporation of both redox and ...stereochemical relays during the design of this synthesis resulted in efficient access to more than 500 milligrams of a key precursor toward ouabagenin—and ultimately ouabagenin itself—and the discovery of innovative methods for carbon-hydrogen (C-H) and carbon-carbon activation and carbon-oxygen bond homolysis. Given the medicinal relevance of the cardenolides in the treatment of congestive heart failure, a variety of ouabagenin analogs could potentially be generated from the key intermediate as a means of addressing the narrow therapeutic index of these molecules. This synthesis also showcases an approach to bypass the historically challenging problem of selective C-H oxidation of saturated carbon centers in a controlled fashion.
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