Gary M. Gallego

Strain-release amination

Opening one ring to tack on another Curious chemists have long sought to learn just how tightly carbon atoms can be bound together. For instance, its possible to form a bond between two opposite corners of an already strained four-membered ring to make an edge-sharing pair of triangles. Gianatassio et al. have now devised a general use for these and related molecular curiosities. They show that appropriately modified nitrogen centers can pop open the most highly strained bond, leaving the more modestly strained ring motif intact. In this way, small rings can emerge as a convenient diversifying element in compounds, including new pharmaceutical candidates. Science, this issue p. 241 Strained rings are appended to compounds of pharmaceutical interest through the use of even more highly strained precursors. To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C–C and C–N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation.

Network Analysis Guided Synthesis of Weisaconitine D and Liljestrandinine

General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three subfamilies of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites.

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.

Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-Ethyl-1α-hydroxy-17-veratroyldictyzine, and Paniculamine

The denudatine-type diterpenoid alkaloids cochlearenine, N-ethyl-1α-hydroxy-17-veratroyldictyzine, and paniculamine have been synthesized for the first time (25, 26, and 26 steps from 16, respectively). These syntheses take advantage of a common intermediate (8) that we have previously employed in preparing aconitine-type natural products. The syntheses reported herein complete the realization of a unified strategy for the preparation of C20, C19, and C18 diterpenoid alkaloids.

Synthesis of the bridging framework of phragmalin-type limonoids.

An efficient synthesis of the octahydro-1H-2,4-methanoindene core of phragmalin-type limonoids, such as xyloccensins O and P, is reported. The success of the synthetic route is predicated on the use of network analysis in the retrosynthetic analysis and a Diels-Alder reaction for the synthesis of a key hydrindanone derivative.

Rh(I)-catalyzed enantioselective intramolecular hydroarylation of unactivated ketones with aryl pinacolboronic esters

Aryl pinacolboronic esters, which are robust and easily handled boronic acid derivatives, effectively add in an intramolecular 1,2 fashion into unactivated ketone groups in the presence of the rhodium complexes [Rh(cod)(MeCN)2]BF4 and a tertiary amine base or [Rh(cod)(OH)]2 and bisphosphine ligands. The latter set of conditions has been utilized in the enantioselective synthesis of indanols bearing tertiary alcohol groups. The overall transformation serves as a complement to the use of boronic acids as well as traditional nucleophiles such as Grignards, zinc reagents and lithium reagents for enantioselective, intramolecular additions to unactivated ketones, especially those additions which require nucleophilic partners that need to be handled over multiple steps.

Modular radical cross-coupling with sulfones enables access to sp3-rich (fluoro)alkylated scaffolds

A sulfur matchmaker for fluorous coupling Fluorination is a burgeoning technique for fine-tuning the properties of pharmaceutical compounds. Unfortunately, the cross-coupling reactions widely used to make carbon-carbon bonds in drug research can be tripped up by fluorine substituents. Merchant et al. report a class of easily prepared, solid sulfone compounds that engage in nickel-catalyzed coupling of their fluoroalkyl groups with aryl zinc reagents. These sulfones considerably simplify the synthetic routes to fluorinated analogs that would previously have required multistep strategies focused strictly on the fluorination protocol. Science, this issue p. 75 Stable sulfone compounds facilitate introduction of fluoroalkyl substituents into targets for medicinal chemistry research. Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron–induced variants of this reaction class have proven particularly useful in the formation of C(sp2)–C(sp3) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method’s tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.

A Unifying Synthesis Approach to the C18‒, C19‒, and C20‒Diterpenoid Alkaloids

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C18, C19, and C20 families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C18 (weisaconitine D), one C19 (liljestrandinine), and three C20 (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

A Copper-Mediated Conjugate Addition Approach to Analogs of Aconitine-Type Diterpenoid Alkaloids

A copper-mediated conjugate addition of electron-rich aryl groups into a complex vinyl nitrile using arylmagnesium bromides is reported. The conjugate addition adducts were advanced toward the synthesis of designed aconitine-type analogues. The variation in oxygenation patterns on the arene coupling partner, introduced through the current conjugate addition approach, may ultimately provide insight into structure-activity relationships of the diterpenoid alkaloids.