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.

Regio- and Enantioselective Synthesis of Trifluoromethyl-Substituted Homoallylic α-Tertiary NH2 -Amines by Reactions Facilitated by a Threonine-Based Boron-Containing Catalyst.

A method for catalytic regio- and enantioselective synthesis of trifluoromethyl-substituted and aryl-, heteroaryl-, alkenyl-, and alkynyl-substituted homoallylic α-tertiary NH2 -amines is introduced. Easy-to-synthesize and robust N-silyl ketimines are converted to NH-ketimines in situ, which then react with a Z-allyl boronate. Transformations are promoted by a readily accessible l-threonine-derived aminophenol-based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl boronates, which may contain an alkyl-, a chloro-, or a bromo-substituted Z-alkene, can either be purchased or prepared by catalytic stereoretentive cross-metathesis. What is more, Z-trisubstituted allyl boronates may be used. Various chemo-, regio-, and diastereoselective transformations of the α-tertiary homoallylic NH2 -amine products highlight the utility of the approach; this includes diastereo- and regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.

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.

γ-, Diastereo-, and Enantioselective Addition of MEMO-Substituted Allylboron Compounds to Aldimines Catalyzed by Organoboron-Ammonium Complexes.

The first catalytic, broadly applicable, efficient, γ-, diastereo-, and enantioselective method for addition of O-substituted allyl-B(pin) compounds to phosphinoylimines (MEM=methoxyethoxymethyl, pin=pinacolato) is presented. The identity of the most effective catalyst and the optimal protecting group for the organoboron reagent were determined by consideration of the steric and electronic requirements at different stages of the catalytic cycle, namely, the generation of the chiral allylboronate, the subsequent 1,3-borotropic shift, and the addition step. Aryl-, heteroaryl-, alkenyl- and alkyl-substituted vicinal phosphinoylamido MEM-ethers were thus accessed in 57-92 % yield, 89:11 to >98:2 γ:α selectivity, 76:24-97:3 diastereomeric ratio, and 90:10-99:1 enantiomeric ratio. The method is scalable, and the phosphinoyl and MEM groups may be removed selectively or simultaneously. Utility is highlighted by enantioselective synthesis of an NK-1 receptor antagonist.

Practical, Broadly Applicable, α-Selective, Z-Selective, Diastereoselective, and Enantioselective Addition of Allylboron Compounds to Mono-, Di-, Tri-, and Polyfluoroalkyl Ketones.

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 and α- and Z-selective when an E-allylboronate compound was used, but enantioselectivities were lower. 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 and offer insight into different selectivity profiles.