Alkyl carboxylic acids are ubiquitous in all facets of chemical science, from natural products to polymers, and represent an ideal starting material with which to forge new connections. This study ...demonstrates how the same activating principles used for decades to make simple C–N (amide) bonds from carboxylic acids with loss of water can be used to make C–C bonds through coupling with dialkylzinc reagents and loss of carbon dioxide. This disconnection strategy benefits from the use of a simple, inexpensive nickel catalyst and exhibits a remarkably broad scope across a range of substrates (>70 examples).
Molecular complexity for a synthetic organic chemist is difficult to define, though intuitively known. Despite the importance of this concept, the quantitative assessment of complexity within organic ...chemistry has remained a challenge. We report here on the development of an approach for generating a unique complexity index, which is reflective of both intrinsic molecular complexity and extrinsic synthetic complexity. This index is based on a community's perception of complexity, within the context of current technology, calculating a molecule's current complexity. Our approach allows for a direct comparison between molecules, the analysis of trends within research programs, it enables an assessment (and comparison) of new synthetic approaches to known molecules and is capable of following a molecule's apparent complexity as it changes over time.
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.
We report that Ni(COD)(DQ) (COD=1,5‐cyclooctadiene, DQ=duroquinone), an air‐stable 18‐electron complex originally described by Schrauzer in 1962, is a competent precatalyst for a variety of ...nickel‐catalyzed synthetic methods from the literature. Due to its apparent stability, use of Ni(COD)(DQ) as a precatalyst allows reactions to be conveniently performed without use of an inert‐atmosphere glovebox, as demonstrated across several case studies.
Old complex, new tricks: Ni(COD)(DQ) (COD=1,5‐cyclooctadiene, DQ=duroquinone) is a remarkably stable Ni0‐‐olefin complex first described in the 1960s. Its ability to serve as a precatalyst for a variety of nickel‐catalyzed reactions is demonstrated.
The ability to procure useful quantities of a molecule by simple, scalable routes is emerging as an important goal in natural product synthesis. Approaches to molecules that yield substantial ...material enable collaborative investigations (such as SAR studies or eventual commercial production) and inherently spur innovation in chemistry. As such, when evaluating a natural product synthesis, scalability is becoming an increasingly important factor. In this
Highlight
, we discuss recent examples of natural product synthesis from our laboratory and others, where the preparation of gram-scale quantities of a target compound or a key intermediate allowed for a deeper understanding of biological activities or enabled further investigational collaborations.
In this
Highlight
, we discuss recent examples of natural product synthesis from our laboratory and others, where the preparation of gram-scale quantities of a target compound or a key intermediate allowed for a deeper understanding of biological activities or enabled further investigational collaborations. (Picture courtesy of Frank Fang of Eisai Inc.)
New methods and strategies for the direct functionalization of C-H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and ...materials. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C-H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as "classics". Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium). These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C-H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C-H oxidation (demonstrated on 100 grams), enabling the adoption of this C-H oxidation strategy in large-scale industrial settings without substantial environmental impact.
Here we report the development of a versatile 3-acetylamino-2-hydroxypyridine class of ligands that promote meta-C–H arylation of anilines, heterocyclic aromatic amines, phenols, and 2-benzyl ...heterocycles using norbornene as a transient mediator. More than 120 examples are presented, demonstrating this ligand scaffold enables a wide substrate and coupling partner scope. Meta-C–H arylation with heterocyclic aryl iodides as coupling partners is also realized for the first time using this ligand. The utility for this transformation for drug discovery is showcased by allowing the meta-C–H arylation of a lenalidomide derivative. The first steps toward a silver-free protocol for this reaction are also demonstrated.
Pd(II)-catalyzed γ-C(sp3)–H arylation of primary amines is realized by using 2-hydroxynicotinaldehyde as a catalytic transient directing group. Importantly, the catalyst and the directing group ...loading can be lowered to 2% and 4% respectively, thus demonstrating high efficiency of this newly designed transient directing group. Heterocyclic aryl iodides are also compatible with this reaction. Furthermore, swift synthesis of 1,2,3,4-tetrahydronaphthyridine derivatives is accomplished using this reaction.
Two named reactions of fundamental importance and paramount utility in organic synthesis have been reinvestigated, the Barton decarboxylation and Giese radical conjugate addition. ...N‐hydroxyphthalimide (NHPI) based redox‐active esters were found to be convenient starting materials for simple, thermal, Ni‐catalyzed radical formation and subsequent trapping with either a hydrogen atom source (PhSiH3) or an electron‐deficient olefin. These reactions feature operational simplicity, inexpensive reagents, and enhanced scope as evidenced by examples in the realm of peptide chemistry.
Simple, thermal, and practical Barton‐type decarboxylation and decarboxylative Giese addition have been developed based on nickel‐catalyzed fragmentation of N‐hydroxyphthalimide redox active esters. The operational simplicity and chemoselectivity of these reactions allow for expedient preparations of various building blocks and late stage modifications of complex molecules.
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