Organofluorine compounds are central to modern chemistry, and broadly applicable transformations that generate them efficiently and enantioselectively are in much demand. Here we introduce efficient catalytic methods for additions of allyl and allenyl organoboron reagents to fluorine-substituted ketones. These reactions are facilitated by readily and inexpensively available catalysts and deliver versatile and otherwise difficult-to-access tertiary homoallylic alcohols in up to 98% yield and >99:1 enantiomeric ratio. Utility is highlighted by a concise enantioselective approach to synthesis of anti-parasitic drug Bravecto™ (presently sold as the racemate). Different forms of ammonium-organofluorine interactions play a key role in controlling enantioselectivity. The greater understanding of various non-bonding interactions afforded by these studies should facilitate future development of transformations involving fluoro-organic entities.
Catalytic allylboron additions to aldimines are presented for which small amounts of Zn(OMe)2 serve as co-catalyst to accelerate allyl exchange and 1,3-borotropic shift processes. Low yielding and moderately α-, and diastereoselective reactions are thus turned into highly efficient, γ-, diastereo- and enantioselective transformations that exhibit considerable scope.
A practical method for enantioselective synthesis of fluoroalkyl-substituted Z-homoallylic tertiary alcohols has been developed. Reactions may be performed with ketones containing a polylfluoro-, trifluoro-, difluoro- and monofluoroalkyl group along with an aryl, a heteroaryl, an alkenyl, an alkynyl, or an alkyl substituent. Readily accessible unsaturated organoboron compounds serve as reagents. Transformations were performed with 0.5–2.5 mol % of a boron-based catalyst, generated in situ from a readily accessible valine-derived aminophenol and a Z- or an E-γ-substituted boronic acid pinacol ester. With a Z organoboron reagent, additions to trifluoromethyl and polyfluoroalkyl ketones proceeded in 80–98% yield, 97:3 to >98:2 α:γ selectivity, >95:5 Z:E selectivity and 81:19 to >99:1 enantiomeric ratio. In notable contrast to reactions with unsubstituted allylboronic acid pinacol ester, additions to ketones with a mono- or a difluoromethyl group were highly enantioselective as well. Transformations were similarly efficient, α- and Z-selective when an E-allylboronate compound was used, but enantioselectivities were lower and, in certain cases, the opposite enantiomer was favored (up to 4:96 er). With a racemic allylboronate reagent that contains an allylic stereogenic center, additions were exceptionally α-selective, affording products, expected from γ-addition of a crotylboron compound, in up to 97% yield, 88:12 diastereomeric ratio and 94:6 enantiomeric ratio. Utility is highlighted by gram scale preparation of representative products through transformations that were performed without exclusion of air or moisture, and through applications in stereoselective olefin metathesis where Z-alkene substrates are required. Mechanistic investigations aided by computational (DFT) studies were carried out and offer insight into different selectivity profiles.
This paper describes an intermolecular crossselective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electrondeficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, and spiro[3.3]heptane motifs, which are of prime interest in medicinal chemistry as gem-dimethyl and carbonyl bioisosteres. A variety of further transformations of the initial cycloadducts are demonstrated to highlight the versatility of the products and enable selective access to either of a syn-or an anti-diastereoisomer through kinetic or thermodynamic epimerization, respectively. Mechanistic experiments and DFT calculations suggest that this reaction proceeds through a sensitized energy transfer pathway.
An operationally simple in situ protection/ deprotection strategy that significantly expands the scope of kinetically controlled catalytic Z-and Eselective olefin metathesis is introduced. Prior to the addition of as ensitive Mo-or Ru-based complex, treatment of ah ydroxy-o racarboxylic-acid-containing olefin with commercially available HB(pin) or readily accessible HB(trip) 2 (pin = pinacolato,t rip = 2,4,6-tri(isopropyl)phenyl) for 15 min is sufficient for efficient generation of ad esired product. Routine workup leads to quantitative deprotection. Ar ange of stereochemically defined Z-and E-alkenyl chlorides, bromides,f luorides,a nd boronates or Z-trifluoromethyl-substituted alkenes with ah ydroxy or carboxylic acid group were thus prepared in 51-97 %y ield with 93 to > 98 %s tereoselectivity.W ea lso show that, regardless of whether apolar functional unit is present or not, as mall amount of HB(pin) may be used to remove residual water,s ignificantly enhancing efficiency.
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