Asymmetric Access to Boryl-Substituted Vicinal Aminoalcohols through Cu-Catalyzed Reductive Coupling

Abstract

Herein, we report the development of a Cu-catalyzed enantioselective borylative aminoallylation of aldehydes using a N-substituted allene to access boryl-substituted 1,2-aminoalcohol synthons for diversification to chiral heteroatom-rich organic compounds. The reported reaction provides access to several different substitution patterns of chiral 1,2-aminoalcohol products from the same readily available starting materials with high diastereo- and enantioselectivity.

Development of regiodivergent asymmetric reductive coupling reactions of allenamides to access heteroatom-rich organic compounds

“…90) that offers significant opportunities for further functionalization due to the vast diversity of transformations the C-B bond can undergo (Scheme 16). 49 While borylative Cu-catalysed enantioselective reductive coupling reactions of carbon-substituted allenes using both aldehyde or imine electrophiles was initially reported by the groups of Hoveyda 111 and Procter, 112 respectively, reactions employing N-substituted allenes have been less developed 113,114 prior to our work. 49 Enantioselective Cu-catalysed borylative reductive coupling of allenimide 78 with aldehyde electrophiles was identified to proceed in high stereoselectivities using Ph-BPE (L2) as ligand to provide intermediate 91 (Scheme 17).…”

“…111 In contrast, the turnover in diastereoselectivity with N -phthaloyl derived allene 78 was rationalized through a catalyst directing effect by the N -phthaloyl group ( N -98 ) to favour nucleophilic Cu-intermediate N -99 having E -alkene geometry that may also benefit from carbonyl lone-pair donation into the vacant boron p-orbital. 49 Addition of N -99 to aldehyde through N -TS leads to the observed anti -stereocontrol in reactions employing allene 78 . As a result, this demonstrates that not only can directing groups on the allene coupling partner be used to control regioselectivity (Fig.…”

“…1). [43][44][45][46][47][48][49][50] As a result, we have primarily focused on accessing coupling products at C1 and C3 of the hypothetical starting material 10 (e.g. 11 and 13, respectively) since these products are typically more challenging to access due to the dissonant charge affinity [9][10][11] produced by the relationship of the two electron-withdrawing heteroatom substituents.…”

“…90 ) that offers significant opportunities for further functionalization due to the vast diversity of transformations the C–B bond can undergo (Scheme 16). 49…”

“…While borylative Cu-catalysed enantioselective reductive coupling reactions of carbon-substituted allenes using both aldehyde or imine electrophiles was initially reported by the groups of Hoveyda 111 and Procter, 112 respectively, reactions employing N -substituted allenes have been less developed 113,114 prior to our work. 49 Enantioselective Cu-catalysed borylative reductive coupling of allenimide 78 with aldehyde electrophiles was identified to proceed in high stereoselectivities using Ph-BPE ( L2 ) as ligand to provide intermediate 91 (Scheme 17). This intermediate was found to be quite sensitive to protonolysis during silica gel chromatography, and therefore, further functionalization reactions of the C–B moiety were developed using telescoped processes through direct transformation of crude 91 .…”