Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions

Abstract

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C-H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si-H bonds to yield an oxophilic silylium (RSi) equivalent along with a reducing (H) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure-activity relationships.

Tris(pentafluorophenyl)borane-Catalyzed Reactions Using Silanes

“…This phenol was needed for an oxidative dearomatization to give a cyclohexadieneone intermediate primed for a tandem bis-radical cyclization to give the [3.3.1]-bicyclic framework of the natural product family. BCF was also applied to the modification of complex bioactive compounds such as natural products and drugs to probe structure-activity relationships [38].…”

Reductive Deamination with Hydrosilanes Catalyzed by B(C6F5)3

“…4 aa is formally composed of amine 1 aa and Piers borane HB(C 6 F 5 ) 2 and can also be synthesized in quantitative yield within a few minutes at room temperature by the reaction of 1 aa and 1.0 equiv of HB(C 6 F 5 ) 2 (not shown). Apparently, B(C 6 F 5 ) 3 and PhSiH 3 underwent the known exchange of substituents, [15] and the formation of C 6 F 5 (Ph)SiH 2 (5) was confirmed spectroscopically; the 86 % yield of 5 was estimated by 19 F NMR spectroscopy (see the Supporting Information for details). The deaminated product 2 a did only form in 2 % yield, and we showed that 20 mol % of Piers borane cannot promote the deamination of 1 aa at 120 8C with 4.0 equiv PhSiH 3 as the reductant (not shown).…”

“…Employing various boron Lewis acid/hydrosilane combinations, GagnØ showcased the impressive chemoand regioselectivity of this methodology when applied to complex molecules. [5] Morandi [6] and our laboratory [7] also contributed to this field. We asked ourselves whether reductive deamination of 18, 28, and 38 amines would be possible in the same manner (Scheme 1, top right).…”

Fluorescent Lewis Adducts: A Refined Guide for Lewis Acidity

“…23 In fact, a recent example by Gagné shows distinct differences in chemoselectivity when applying B(C6F5)3 or B(3,5-(CF3)C6H3)3 as a Lewis acid catalyst for the reduction of natural products and sugars. 24,25 However, measurements of experimental Lewis acid strength for numerous derivatives have been inconsistent. 26 It is evident that due to the high popularity of boranes, applying the FLA method would be a valuable exercise.…”