Click processes orthogonal to CuAAC and SuFEx forge selectively modifiable fluorescent linkers.

The appeal of catalytic click chemistry is largely due to the copper-catalysed azide-alkyne cycloaddition (CuAAC) process, which is orthogonal to the more recently introduced sulfur-fluoride exchange (SuFEx). However, the triazole rings generated by CuAAC are not readily modifiable, and SuFEx connectors cannot be selectively functionalized, attributes that would be attractive in a click process. Here we introduce bisphosphine-copper-catalysed phenoxydiazaborinine formation (CuPDF), a link-and-in situ modify strategy for merging a nitrile, an allene, a diborane and a hydrazine. We also present copper- and palladium-catalysed quinoline formation (Cu/PdQNF), which is applicable in aqueous media, involving an aniline as the modifier. CuPDF and Cu/PdQNF are easy to perform and deliver robust, alterable and tunable fluorescent hubs. CuPDF and Cu/PdQNF are orthogonal to SuFEx and CuAAC, despite the latter and CuPDF also being catalysed by an organocopper species. These advantages were applied to protecting group-free syntheses of sequence-defined branched oligomers, a chemoselectively amendable polymer, three drug conjugates and a two-drug conjugate.

Streamlined Strategy for Scalable and Enantioselective Total Syntheses of the Eburnane Alkaloids.

A general, concise, and efficient strategy for the enantioselective synthesis of the eburnane alkaloid family of natural products is disclosed. Specifically, 13 members of the natural product family were prepared from commercially available and inexpensive starting materials. The brevity and modularity of the route are largely on account of a two-phase synthesis logic and a key catalytic enantioconvergent cross-coupling to establish the C20 stereogenic center. The strategies described here are expected to facilitate in-depth biological studies and provide access to new anticancer eburnane analogues.

Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre.

Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl- and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereo- and enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl- and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.

Convergent Synthesis of the C1-C29 Framework of Amphidinolide F.

The complete carbon framework of the macrocyclic marine natural product amphidinolide F has been prepared by a convergent synthetic route in which three fragments of similar size and complexity have been coupled. Key features of the syntheses of the fragments include the stereoselective construction of the tetrahydrofuran in the C1-C9 fragment by oxonium ylide (free or metal-bound) formation and rearrangement triggered by the direct generation of a rhodium carbenoid from 1-sulfonyl-1,2,3-triazole, the highly diastereoselective aldol reaction between a boron enolate and an aldehyde with 1,4-control to prepare the C10-C17 fragment, and the formation of the tetrahydrofuran in the C18-C29 fragment by intramolecular nucleophilic ring opening of an epoxide with a hydroxyl group under acidic conditions.

E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing.

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

Streamlined Catalytic Enantioselective Synthesis of α-Substituted ß,γ-Unsaturated Ketones and Either of the Corresponding Tertiary Homoallylic Alcohol Diastereomers.

A widely applicable, practical, and scalable strategy for efficient and enantioselective synthesis of ß,γ-unsaturated ketones that contain an α-stereogenic center is disclosed. Accordingly, aryl, heteroaryl, alkynyl, alkenyl, allyl, or alkyl ketones that contain an α-stereogenic carbon with an alkyl, an aryl, a benzyloxy, or a siloxy moiety can be generated from readily available starting materials and by the use of commercially available chiral ligands in 52-96% yield and 93:7 to >99:1 enantiomeric ratio. To develop the new method, conditions were identified so that high enantioselectivity would be attained and the resulting α-substituted NH-ketimines, wherein there is strong C═N → B(pin) coordination, would not epimerize before conversion to the derived ketone by hydrolysis. It is demonstrated that the ketone products can be converted to an assortment of homoallylic tertiary alcohols in 70-96% yield and 92:8 to >98:2 dr-in either diastereomeric form-by reactions with alkyl-, aryl-, heteroaryl-, allyl-, vinyl-, alkynyl-, or propargyl-metal reagents. The utility of the approach is highlighted through transformations that furnish other desirable derivatives and a concise synthesis route affording more than a gram of a major fragment of anti-HIV agents rubriflordilactones A and B and a specific stereoisomeric analogue.

A Catalytic Approach for Enantioselective Synthesis of Homoallylic Alcohols Bearing a Z-Alkenyl Chloride or Trifluoromethyl Group. A Concise and Protecting Group-Free Synthesis of Mycothiazole.

A protecting group-free strategy is presented for diastereo- and enantioselective routes that can be used to prepare a wide variety of Z-homoallylic alcohols with significantly higher efficiency than is otherwise feasible. The approach entails the merger of several catalytic processes and is expected to facilitate the preparation of bioactive organic molecules. More specifically, Z-chloro-substituted allylic pinacolatoboronate is first obtained through stereoretentive cross-metathesis between Z-crotyl-B(pin) (pin = pinacolato) and Z-dichloroethene, both of which are commercially available. The organoboron compound may be used in the central transformation of the entire approach, an α- and enantioselective addition to an aldehyde, catalyzed by a proton-activated, chiral aminophenol-boryl catalyst. Catalytic cross-coupling can then furnish the desired Z-homoallylic alcohol in high enantiomeric purity. The olefin metathesis step can be carried out with substrates and a Mo-based complex that can be purchased. The aminophenol compound that is needed for the second catalytic step can be prepared in multigram quantities from inexpensive starting materials. A significant assortment of homoallylic alcohols bearing a Z-F3C-substituted alkene can also be prepared with similar high efficiency and regio-, diastereo-, and enantioselectivity. What is more, trisubstituted Z-alkenyl chloride moiety can be accessed with similar efficiency albeit with somewhat lower α-selectivity and enantioselectivity. The general utility of the approach is underscored by a succinct, protecting group-free, and enantioselective total synthesis of mycothiazole, a naturally occurring anticancer agent through a sequence that contains a longest linear sequence of nine steps (12 steps total), seven of which are catalytic, generating mycothiazole in 14.5% overall yield.

Catalytic Enantioselective Boryl and Silyl Substitution with Trifluoromethyl Alkenes: Scope, Utility, and Mechanistic Nuances of Cu-F ß-Elimination.

Catalytic enantioselective methods are introduced that allow access to a variety of allyl boronates and silanes that contain a difluoroalkene unit; the resulting products may be used for the preparation of organofluorine compounds in high enantiomeric purity. Furthermore, a number of key mechanistic aspects of the transformations have been investigated and analyzed. Thus, first, an NHC-Cu-catalyzed method for boryl substitution with F3C-substituted alkenes is introduced. These processes, unlike the previously reported strategies, are applicable to alkyl as well as aryl substituted substrates, afford allyl boronates bearing a difluoroalkene moiety (up to 98% yield and 95:5 er). Second, the corresponding silyl substitutions, the first reported cases of their kind, are presented (up to 94% yield and 97:3 er). Third, experimental and computational (DFT) investigations are described that shed light on key mechanistic aspects of the catalytic processes. Evidence (X-ray structures of Cu-alkyl intermediates and kinetic studies) is put forth illustrating that the initial Cu-boryl and Cu-silyl addition is significantly faster than the ensuing Cu-F elimination, and that the latter step can be facilitated by either a mild Lewis acid (e.g., a Li or Na cation) or a nucleophilic promoter (e.g., an alkoxide). These findings together with DFT studies demonstrate that Cu-F ß-elimination probably proceeds with anti-stereochemistry. Representative cases of ways through which the new mechanistic understanding may be used to rationalize previously disclosed findings, significantly improve a transformation, or develop new diastereo- and enantioselective catalytic methods are provided. For example, an explanation is provided regarding why bisphosphine-Cu complexes do not efficiently promote boryl substitutions with aryl-substituted substrates, but the corresponding silyl substitutions are facile, and how the size of a ligand can impact regioselectivity and efficiency.

Different Strategies for Designing Dual-Catalytic Enantioselective Processes: From Fully Cooperative to Non-cooperative Systems.

An emerging area of research in chemistry requires that we learn how to manage the characteristics of a pair of co-catalysts so that a transformation proceeds as we wish it to. These are processes during which one catalyst first generates a non-isolable intermediate, which then in situ undergoes a reaction that is promoted by a different catalyst. This scenario raises several design issues. Since co-catalysts often have overlapping functions, what if there is an exchange of ligands between two organometallic catalysts? How can we be certain that a co-catalyst reacts specifically with a particular intermediate? What if the less reactive co-catalyst must engage first, and the one that is more active needs to wait its turn? How might we orchestrate the proper sequence of events? While many dual-catalytic processes have been introduced and reviews are available, there are subtle yet crucial distinguishing attributes that remain unappreciated. While the terms "dual-catalysis" and "cooperative catalysis" are often used interchangeably, on many occasions the catalysts are not entirely cooperative. Here, we will discuss how chemists have been able to harmonize the opposing functions of catalysts to achieve high efficiency and/or stereoselectivity. We will show that the progress achieved thus far is likely the preamble to the future development of non-orthogonal multi-catalytic processes (i.e., transformations involving several catalysts that are not inherently cooperative) where the order with which each catalyst enters the fray will demand additional innovative strategies.

Catalytic Enantioselective Synthesis of Allylic Boronates Bearing a Trisubstituted Alkenyl Fluoride and Related Derivatives.

The first catalytic method for diastereo- and enantioselective synthesis of allylic boronates bearing a Z-trisubstituted alkenyl fluoride is disclosed. Boryl substitution is performed with either a Z- or E-allyldifluoride and is catalyzed by bisphosphine/Cu complexes, affording products in up to 99 % yield with >98:2 Z/E selectivity and 99:1 enantiomeric ratio. A variety of subsequent modifications are feasible, and notable examples are diastereoselective additions to aldehydes/aldimines to access homoallylic alcohols/amines containing a fluorosubstituted stereogenic quaternary center.

Delayed catalyst function enables direct enantioselective conversion of nitriles to NH2-amines.

Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine. Successful implementation requires that competing copper-based catalysts be present simultaneously and that the slower-forming and less reactive one engages first. This challenge was addressed by incorporation of a nonproductive side cycle, fueled selectively by inexpensive additives, to delay the function of the more active catalyst. The utility of this approach is highlighted by its application to the efficient preparation of the anticancer agent (+)-tangutorine.

Catalytic diastereo- and enantioselective additions of versatile allyl groups to N-H ketimines.

There are many biologically active organic molecules that contain one or more nitrogen-containing moieties, and broadly applicable and efficient catalytic transformations that deliver them diastereoselectively and/or enantioselectively are much sought after. Various methods for enantioselective synthesis of α-secondary amines are available (for example, from additions to protected/activated aldimines), but those involving ketimines are much less common. There are no reported additions of carbon-based nucleophiles to unprotected/unactivated (or N-H) ketimines. Here, we report a catalytic, diastereo- and enantioselective three-component strategy for merging an N-H ketimine, a monosubstituted allene and B2(pin)2, affording products in up to 95% yield, >98% diastereoselectivity and >99:1 enantiomeric ratio. The utility of the approach is highlighted by synthesis of the tricyclic core of a class of compounds that have been shown to possess anti-Alzheimer activity. Stereochemical models developed with the aid of density functional theory calculations, which account for the observed trends and levels of enantioselectivity, are presented.

Kinetically controlled E-selective catalytic olefin metathesis.

A major shortcoming in olefin metathesis, a chemical process that is central to research in several branches of chemistry, is the lack of efficient methods that kinetically favor E isomers in the product distribution. Here we show that kinetically E-selective cross-metathesis reactions may be designed to generate thermodynamically disfavored alkenyl chlorides and fluorides in high yield and with exceptional stereoselectivity. With 1.0 to 5.0 mole % of a molybdenum-based catalyst, which may be delivered in the form of air- and moisture-stable paraffin pellets, reactions typically proceed to completion within 4 hours at ambient temperature. Many isomerically pure E-alkenyl chlorides, applicable to catalytic cross-coupling transformations and found in biologically active entities, thus become easily and directly accessible. Similarly, E-alkenyl fluorides can be synthesized from simpler compounds or more complex molecules.

Synthesis of the A-D Ring System of the Gambieric Acids.

The A-D fragment of gambieric acids A and C has been synthesized using an asymmetric Tsuji-Trost allylation reaction to couple the two key segments. The A ring fragment has been prepared by a short and highly efficient route involving diastereoselective Lewis acid mediated alkylation of an acetal. Iterative ring-closing metathesis reactions have been used to construct cyclic ethers and assemble the tricyclic B-D fragment.

Synthesis of cyclopropyl-substituted furans by brønsted Acid promoted cascade reactions.

Chloroacetic acid promotes an efficient and diastereoselective intramolecular cascade reaction of electron-deficient ynenones to deliver products featuring a 2,3,5-trisubstituted furan bearing a fused cyclopropyl substituent at the 5-position. Synthetically relevant polycyclic building blocks featuring rings of various sizes and heteroatoms have been synthesized in high yield using this mild acid-catalyzed reaction.

Total syntheses of amphidinolides T1, T3, and T4.

Concise and high-yielding total syntheses of amphidinolides T1, T3, and T4 have been completed using an alkynyl macrolactone as a common late-stage intermediate. The required α-hydroxy ketone motif was installed by sequential alkyne hydrosilylation, epoxidation, and Fleming-Tamao oxidation. An oxonium ylide rearrangement formed the trisubstituted tetrahydrofuran core found in the natural products.