Enantioselective construction of remote tertiary carbon–fluorine bonds

Abstract

The carbon-fluorine bond engenders distinctive physicochemical properties and significant changes to general reactivity, which have impacted molecular design in material science, agrochemicals, and pharmaceutical research. These unique features are generally derived from fluorine having the highest electronegativity coupled to an enhanced bond strength of the C-F bond compared to a C-H bond. As a result, C-F bonds are often leveraged as replacements for C-H bonds when the latter presents a liability at a saturated (sp 3 ) carbon centre especially for benzylic C-H bonds prone to metabolic oxidation. In this context, the development of catalytic, enantioselective methods to set stereocenters containing a benzylic C-F bond has been an important and rapidly evolving goal in synthetic chemistry. There have been notable advances enabling the construction of secondary stereocenters containing both a C-F and a C-H bond on the same carbon. In contrast, there are significantly fewer synthetic strategies defined for accessing stereocenters that incorporate a tertiary C-F bond, especially those remote from pre-existing activating groups. Herein, we report a general method that establishes C-F tertiary, benzylic stereocenters by forging a C-C bond via a Pd-catalyzed enantioselective Heck reaction of acyclic alkenyl fluorides with arylboronic acids. This method provides a platform to rapidly incorporate significant functionality about the benzylic tertiary fluoride by virtue of the diversity of both reaction partners as well as the ability to install the stereocenters remotely from pre-existing functional groups.The catalytic, enantioselective formation of tertiary C-F bonds has traditionally been accomplished through bond formation adjacent (defined as α) to a pre-existing functional group (Fig. 1A). [1][2][3][4] This is highlighted by: 1) the functionalization of carbonyl derivatives via the reaction of an enolate or an enolate equivalent with either an electrophilic Reprints and permissions information is available at www.nature.com/reprints.

Recent Advances of Catalytic Enantioselective Heck Reactions and Reductive‐Heck Reactions

“…Moreover, the Heck reaction of fluorine‐substituted trisubstituted alkenols with arylboronic acids was also developed to efficiently establish C–F tertiary benzylic stereocenters (Scheme 29d). [ 40 ]…”

Facile Synthesis of Quaternary α-Fluoronitriles by Cobalt-Catalyzed Hydrocyanation of Monofluoroalkenes

“…7 Considering that alkenes served normally as one kind of simple and basal materials for further transformation to diverse complex molecules, we envisioned that monofluoroalkenes may play as a potential molecular platform to construct various monofluorine-containing compounds. 8 As is known, the metal-hydride hydrogen atom transfer (MHAT) process is used as a strong strategy for the hydrofunctionalization of alkenes by an in situ generation of hydrogenated carbon radical or metal species, followed by various radical captures or metal-catalyzed functionalizations. 9 Accordingly, we speculated that a…”

Stereoselective Remote Functionalization via Palladium‐Catalyzed Redox‐Relay Heck Methodologies

“…[49,50] Arylation of trisubstituted (Z)-alkenols (60)c ontaining af luorine substituent on the alkene has also been demonstrated, althought he majority of the investigation focusedo nb-functionalization. [51] Substantially higher catalyst loadings were requiredt og eneratem ore remote fluorinated tertiary stereogenic carbon centers (61), but thesew ere found to proceedi ne xcellent enantioselectivity,w hich diminished slightly with increased chain length (Scheme 18). This methodology enables the straightforward access to enantio-enriched fluorinated buildingb locks, which, in some cases, are knownt oc onfer favorable physicochemical properties in drug molecules.…”

“…Arylation of trisubstituted ( Z )‐alkenols ( 60 ) containing a fluorine substituent on the alkene has also been demonstrated, although the majority of the investigation focused on β‐functionalization [51] . Substantially higher catalyst loadings were required to generate more remote fluorinated tertiary stereogenic carbon centers ( 61 ), but these were found to proceed in excellent enantioselectivity, which diminished slightly with increased chain length (Scheme 18).…”