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.

Catalytic and Stereoselective Transformations with Easily Accessible and Purchasable Allyl and Alkenyl Fluorides.

Stereochemically defined organofluorine compounds are vital to drug discovery and many applicable catalytic strategies have been introduced for accessing these entities stereoselectively. One approach entails incorporation of a fluorine atom (C-F bond formation) or an organofluorine moiety (e.g., CF3 or CF2 H), and another exploits commercially available compounds with one or more fluorine atoms. Here, we present the state-of-the-art regarding the use of alkenyl and allylic fluorides in preparation of stereochemically defined fluoro-organic molecules. Allylic and alkenyl fluorides may be purchased or generated from a commercially available acid, carboxylate salt, ester, aldehyde hydrate, or ketone bearing several fluorine atoms next to a carbonyl group. We underscore the untapped potential of purchasable organofluorine compounds, many allylic and alkenyl fluorides, as launching points for development of stereoselective processes that are of value to therapeutic science.

Cross-metathesis of Allenes. Mechanistic Analysis and Identification of a Ru-CAAC as the Most Effective Catalyst.

The first examples of cross-metathesis between two different allenes is disclosed. First- and second-generation Ru complexes were found to be ineffective, at most affording only oligomeric products. The exception was a first-generation complex bearing a bidentate phenyl isopropoxy ligand (i.e., PCy3 is not released upon initiation), reactions with which afforded a 1,3-disubstituted allenyl boronate in 22% yield. On the basis of mechanistic studies designed to gain deeper understanding of the reasons for the ineffectiveness of different Ru catalysts, it was discovered that phosphine-free Ru-CAAC complexes have the steric and electronic attributes to be highly effective. The results of these investigations pave the way for development of additional olefin metathesis reactions that generate allenes.

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.

Catalytic Enantioselective Synthesis of Amino Skipped Diynes.

The Cu-catalyzed synthesis of nonracemic 3-amino skipped diynes via an enantiodetermining C-C bond formation is described using StackPhos as ligand. Despite challenging issues of reactivity and stereoselectivity inherent to these chiral skipped diynes, the reaction tolerates an extremely broad substrate scope with respect to all components and provides the title compounds in excellent enantiomeric excess. The alkyne moieties are demonstrated here to be useful synthetic handles, and 3-amino skipped diynes are convenient building blocks for enantioselective synthesis.

Gold-catalyzed transformation of unsaturated alcohols.

The use of gold-complexes to activate carbon-carbon π-bonds has become a well-known and highly reliable mode of reactivity for applications in organic synthesis. This review covers the use of gold-catalysts for activation of unsaturated alcohols to effect substitution with concomitant loss of water and is mostly focused on reactions where the π-acidity appears to overcome the inherent Lewis acidity of the complexes for alcohol activation. Select examples from the literature which demonstrate advances made between 2011 and 2014 are presented.

Controlling regiochemistry in the gold-catalyzed synthesis of unsaturated spiroketals.

A novel gold-catalyzed synthesis of unsaturated spiroketals that addresses regioselectivity issues commonly reported in metal-catalyzed spiroketalization of alkynes is reported. The reaction sequence is regulated by an acetonide protecting group which undergoes extrusion of acetone to deliver the desired spiroketals in good yields and diastereoselectivities. The reaction, which is carried out under very mild conditions employing AuCl as the catalyst, should be widely applicable in the synthesis of a broad range of spiroketals.

Pd(II)-catalyzed spiroketalization of ketoallylic diols.

A high-yielding stereoselective method for forming spiroketals from simple ketoallylic diols is reported. Employing catalytic [PdCl2(MeCN)2] in THF at 0 °C, these dehydrative cyclization reactions require only mild conditions to produce vinyl-substituted spiroketals in high yields after brief reaction times with water as the only byproduct. Using this method, the stereochemical information embedded at the nucleophile is transmitted "down-the-chain" and efficiently sets the stereochemistry at both the anomeric carbon atom and the newly formed allylic stereocenter.