Asymmetric Synthesis of α-Aminoboronates via Rhodium-Catalyzed Enantioselective C(sp³)–H Borylation

Abstract

α-Aminoboronic acids, isostructural boron analogues of α-amino acids, have received much attention because of the important biomedical applications implicated for compounds containing this structure. Additionally, the inherent versatility of α-aminoboronic acids as synthetic intermediates through diverse carbon−boron bond transformations makes the efficient synthesis of these compounds highly desirable. Here, we present a Rh-monophosphite chiral catalytic system that enables a highly efficient enantioselective borylation of N-adjacent C(sp 3 )−H bonds for a range of substrate classes including 2-(N-alkylamino)heteroaryls and Nalkanoyl-or aroyl-based secondary or tertiary amides, some of which are pharmaceutical agents or related compounds. Various stereospecific transformations of the enantioenriched α-aminoboronates, including Suzuki−Miyaura coupling with aryl halides and the Rh-catalyzed reaction with an isocyanate derivative of α-amino acid, affording a new peptide chain elongation method, have been demonstrated. As a highlight of this work, the borylation protocol was successfully applied to the catalyst-controlled site-selective and stereoselective C(sp 3 )−H borylation of an unprotected dipeptidic compound, allowing remarkably streamlined synthesis of the anti-cancer drug molecule bortezomib and offering a straightforward route for the synthesis of privileged molecular architectures.

Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate

“…In a later publication, Sawamura and co-workers investigated ligand L22 further, this time in the context of enantioselective rhodium-catalyzed synthesis of α-aminoboronates. 226 With an appropriate heterocycle present in the substrate, enantioselective functionalization of N -adjacent sp 3 C–H bonds was observed with excellent enantioselectivity. Importantly, however, under the new conditions, the substrate scope could be extended to amides ( Figure 61 a), and the resulting optically enriched α-aminoboronate products ( Figure 61 b) are of interest in the context of medicinal chemistry as amino acid analogues.…”

Iridium‐Catalyzed Regio‐ and Enantioselective Borylation of Unbiased Methylene C(sp3)−H Bonds at the Position β to a Nitrogen Center

“…In stark contrast, there are only two efficient methods for asymmetric α‐C(sp 3 )−H borylation (Scheme 1 a). [12b, 14d] And, while achiral versions of β‐selective reactions have been realized, [19] the enantioselective discrimination of two enantiotopic methylene C(sp 3 )−H necessary for asymmetric, β‐selective C−H borylation is highly challenging. Thus, it is still appealing to develop novel and complementary methods in this area.…”

“…The current method was also compatible with substrates containing transformable groups, such as amide, acetal, and TBS‐protected hydroxy groups. For example, although there are two amide‐directed competitive reaction sites α‐C(sp 3 )−H of piperidine motif [12b, 14d] and β‐C(sp 3 )−H bond of amide [14f] in substrate 1 oa , 3 oa was obtained as the exclusive product in 76 % yield with 83 % ee . Excellent enantioselectivity ( 3 pa : 94 %) and good yields were observed when an acetal group resided on the N ‐alkyl chain.…”

Novel Chiral Ligands‐Enabled Transition‐Metal‐Catalyzed Asymmetric C—H Borylation

“…this asymmetric catalysis was the generation of a monophosphite‐Ir‐tris(boryl) complex that provided a narrow chiral reaction pocket to differentiate the enantiotopic methylene C—H bonds. Just recently, by using the same chiral ligand L1 , Sawamura presented a Rh‐catalyzed enantioselective borylation of N‐adjacent C(sp 3 )—H bonds allowing the preparation of chiral α‐aminoboronates . It's worth mentioning that, this borylation methodology was successfully applied to the synthesis of anti‐cancer drug molecule bortezomib through site‐selective and stereoselective C(sp 3 )—H borylation of an unprotected dipeptidic compound.…”