Stereocontrolled Total Synthesis of (−)‐Stemaphylline

Abstract

Homologation of readily available α‐boryl pyrrolidines with metal carbenoids is especially challenging even when good leaving groups (Cl−) are employed. By performing a solvent switch from Et2O to CHCl3, efficient 1,2‐metalate rearrangement of the intermediate boronate occurs with both halide and ester leaving groups. The methodology was used in the total synthesis of the Stemona alkaloid (−)‐stemaphylline in just 11 steps (longest linear sequence), with high stereocontrol (>20:1 d.r.) and 11 % overall yield. The synthesis also features a late‐stage lithiation–borylation reaction with a tertiary amine containing carbenoid.

Sustainable Asymmetric Organolithium Chemistry: Enantio‐ and Chemoselective Acylations through Recycling of Solvent, Sparteine, and Weinreb “Amine”

“…During a recent study on the synthesis of thioamides from isothiocyanates and organolithium reagents, we noticed that the combination of sparteine and the sustainable solvent cyclopentyl methyl ether (CPME) effectively achieved a high level of stereocontrol (Scheme b). Additionally, this solvent promoted fast lithiations of hindered benzoate esters, as observed by Aggarwal during the synthesis of (−)‐stemaphylline in the presence of the (+)‐sparteine surrogate …”

“…Additionally,t his solvent promoted fast lithiations of hindered benzoate esters, as observedb yA ggarwal during the synthesiso f( À)-stemaphylline in the presenceo ft he (+ +)-sparteine surrogate. [18] Surprisingly,t he Hoppe-Beak approach did not find application to synthesize ketones, and thus its full preparative potential was underestimated. [19] This is quite astounding because enantiomerically enriched a-substituted ketones constitute privileged frameworks across the chemical sciences.…”

Ring‐Opening Lithiation–Borylation of 2‐Trifluoromethyl Oxirane: A Route to Versatile Tertiary Trifluoromethyl Boronic Esters

“…Analysis of the mixture revealed an 8:92 mixture of the desired boronic ester 3a and borinic ester 4a, the latter originating from 1,2-migration of one of the pinacol oxygen atoms (O-migration). Theu nusually strong preference for contra-thermodynamic O-migration over C-migration [15] provided one of many surprises at how the CF 3 group profoundly changes reactivity.A sthe reactivity of boronates can be strongly dependent on solvent, [16] we performed aT HF!toluene solvent exchange after formation of the boronate,w ith subsequent addition of TESOTf at À102 8 8C.…”

Highly Enantiospecific Borylation for Chiral α‐Amino Tertiary Boronic Esters

“…[2, 3] From the success of these compounds, there has been an increased interest in searching a-amino boronate-containing small bioactive molecules (Figure 1).In view of their broad biological activities,s ubstantial efforts have been made to develop synthetic methods for the asymmetric construction of a-aminoboronic acids and their derivatives. [4] Examples include Mattesonsh omologation, [5] sparteine-mediated enantioselective lithiation-borylation, [6] metal-catalyzed and metal-free borylation of imines, [7] Cucatalyzed borylation of enamides, [8] Cu-catalyzed hydroamination of alkenyl dan-boronates, [9] Curtius rearrangement of chiral a-borylcarboxylic acid derivatives, [10] and Ni-catalyzed decarboxylative borylation. [11] These approaches by either use of chiral auxiliaries or asymmetric catalytic transformations have been utilized for the efficient preparation of avariety of a-aminoboronic acid derivatives,whereas they mainly limited to the construction of chiral a-amino secondary boronic esters.Indeed, there have been only alimited number of reports on asymmetric approaches to more sterically congested aamino tertiary boronic esters,w hich involves ap articular challenge for the stereoselective construction of N-substituted quaternary carbon stereogenic centers (Scheme 1).…”