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.

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.

Electronically Activated Organoboron Catalysts for Enantioselective Propargyl Addition to Trifluoromethyl Ketones.

A broadly applicable, practical, scalable, efficient and highly α- and enantioselective method for addition of a silyl-protected propargyl moiety to trifluoromethyl ketones has been developed. Reactions, promoted by 2.0 mol % of a catalyst that is derived in situ from a readily accessible aminophenol compound at ambient temperature, were complete after only 15 minutes at room temperature. The desired tertiary alcohols were isolated in up to 97 % yield and 98.5:1.5 enantiomeric ratio. Alkyl-, alkenyl-, alkynyl-, aryl- or heteroaryl-substituted trifluoromethyl ketones can be used. Utility is highlighted by application to a transformation that is relevant to enantioselective synthesis of BI 653048, a compound active against rheumatoid arthritis.

Practical, efficient, and broadly applicable synthesis of readily differentiable vicinal diboronate compounds by catalytic three-component reactions.

A practical, efficient and broadly applicable catalytic method for synthesis of easily differentiable vicinal diboronate compounds is presented. Reactions are promoted by a combination of PCy3 or PPh3, CuCl and LiOt-Bu and may be performed with readily accessible alkenyl boronate substrates. Through the use of an alkenyl-B(pin) (pin = pinacolato) or alkenyl- B(dan) (dan = naphthalene-1,8-diaminato) starting material and commercially available (pin)B- B(dan) or B2(pin)2 as the reagent, a range of vicinal diboronates, including those that contain a B-substituted quaternary carbon center, may be prepared in up to 91% yield and with >98% site selectivity. High enantioselectivities can be obtained (up to 96:4 er) through the use of commercially available chiral bis-phosphine ligands for reactions that afford mixed diboronate products.

Controllable ROMP Tacticity by Harnessing the Fluxionality of Stereogenic-at-Ruthenium Complexes.

Readily accessible and easy-to-handle Ru complexes capable of generating all-Z polynorbornene and polynorbornadiene by ring-opening metathesis polymerization (ROMP) with controllable selectivity, ranging from ≈50 to ≥95% syndiotactic, are introduced. It is demonstrated that the rate of non-metathesis based polytopal isomerization and levels of syndiotacticity may be fine-tuned by the adjustment of monomer concentration and catalyst's steric and electronic characteristics.

High-value alcohols and higher-oxidation-state compounds by catalytic Z-selective cross-metathesis.

Olefin metathesis catalysts provide access to molecules that are indispensable to physicians and researchers in the life sciences. A persisting problem, however, is the dearth of chemical transformations that directly generate acyclic Z allylic alcohols, including products that contain a hindered neighbouring substituent or reactive functional units such as a phenol, an aldehyde, or a carboxylic acid. Here we present an electronically modified ruthenium-disulfide catalyst that is effective in generating such high-value compounds by cross-metathesis. The ruthenium complex is prepared from a commercially available precursor and an easily generated air-stable zinc catechothiolate. Transformations typically proceed with 5.0 mole per cent of the complex and an inexpensive reaction partner in 4-8 hours under ambient conditions; products are obtained in up to 80 per cent yield and 98:2 Z:E diastereoselectivity. The use of this catalyst is demonstrated in the synthesis of the naturally occurring anti-tumour agent neopeltolide and in a single-step stereoselective gram-scale conversion of a renewable feedstock (oleic acid) to an anti-fungal agent. In this conversion, the new catalyst promotes cross-metathesis more efficiently than the commonly used dichloro-ruthenium complexes, indicating that its utility may extend beyond Z-selective processes.