Synthesis of Highly Enantioenriched C‐Tertiary Amines From Boronic Esters: Application to the Synthesis of Igmesine

Abstract

Tertiary alkylamines are common motifs in many natural products and pharmaceuticals but access to them in enantiomerically enriched form can sometimes present a major challenge. A standard route to these compounds involves the addition of nucleophiles, for example, organometallic reagents [1] or cyanide [2] to ketimines, but other indirect methods have also been reported.[3] Whilst many of these methods have been successful in delivering high levels of stereocontrol, the level of selectivity is highly substratedependent.We recently reported a conceptually new method for the synthesis of tertiary alcohols that routinely delivered more than 98 % ee over a broad range of substrates (Scheme 1).[4] In this process, lithiation of secondary carbamates 1 followed by treatment with boronic esters and subsequent addition of MgBr 2 /MeOH gave the tertiary boronic esters 2, which were finally oxidized to tertiary alcohols in high ee. We reasoned that isolation of the intermediate tertiary boronic esters and subsequent amination could provide a new route to C-tertiary alkylamines in high ee. Whilst amination of primary and even secondary boronic esters had been reported, [5][6][7] the much more challenging tertiary boronic esters had not. We therefore embarked on this study and now report that C-tertiary alkylamines can indeed be obtained in more than 98 % ee using this methodology.Of the reported amination transformations, Mattesons direct conversion of a potassium trifluoroborate salt into an amine [7] turned out to be the most efficient and reliable, [8] and after some modification of the reaction conditions [9] this protocol was ultimately successful. Thus, a broad range of tertiary boronic esters were first converted into the corresponding trifluoroborates 3 and then treated with SiCl 4 and an alkyl azide (Table 1). Using this protocol with benzyl azide 4 a, the tertiary trifluoroborate 3 a was converted into the tertiary benzylamine 5 aa in 94 % yield and 99 % ee (entry 1). The methodology could be extended to other substituted benzylic and alkyl azides (entries 2, 3). In terms of the scope of the tertiary trifluoroborate, hindered alkyl groups (iPr, cHex; entries 4-6) and even diarylalkyl trifluoroborates (entries 7, 8) could all be employed, leading to C-tertiary alkyl amines with very high ee. The latter two examples are noteworthy as the diarylalkyl boron intermediates are especially prone to homolysis and radical recombination but no erosion in ee was observed.Some limitations of the methodology however, were uncovered. For example, the homoallylic trifluoroborate salt 6 only gave the tertiary amine 7 in 14 % yield together with ketone 8 in 75 % yield (Scheme 2, see Supporting Information for a mechanistic discussion on the origin of 8).The para-methoxy analogue of the trifluoroborate 3 f was also ineffective. Since both the meta-methoxy substrate 3 f and the para-methoxybenzylic secondary trifluoroborate salt [10] worked well, it showed that this limitation was specific to the tertiary, electron-rich diaryl trifl...

A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl–Alkyl Cross‐Coupling Reactions

“…Utilization of 5 for the generation of valuable and pharmaceutically relevant tertiary cyclobutylamines was successfully demonstrated, providing the benzyl protected derivative 6 in 70 %yield over two steps. [15] Furthermore,wewere also able to construct quaternary carbon centers using two recently developed methodologies for C(sp 2 ) À C(sp 3 )cross-coupling of boronic esters:r eaction of 5 with 2-lithiofuran and as ubsequent quench with N-bromosuccinimide (NBS) led to cyclobutylated furan derivative 7 in 47 %y ield; [16] whereas an iridium-catalyzed photoredox flow process [17] allowed us to couple 1-isoquinolinecarbonitrile to 5,l eading to cyclobutylated isoquinoline derivative 8 in 49 %yield. Finally,wewere further able to apply this process to the short three-step synthesis of the GABAr eceptor agonist drug, baclofen (10; Scheme 3b).…”

Synthetic Applications and Inversion Dynamics of Configurationally Stable 2-Lithio-2-arylpyrrolidines and -piperidines

“…Removal of the Boc-group using gaseous HCl gave unprotected 9 , with the same sign of specific rotation as that recently reported by Aggarwal for enantiopure deprotected R - 9 . 5f Based on retentive deuteration and methylation, and the recently reported work of O’Brien and Coldham in which the steric course of several such substitutions were characterized, 13 we have assigned all the substitutions reported herein as retentive. Quenching with Me 3 SiCl afforded S - 10 in 88% yield and 96:4 er (entry 3).…”

“…Benzylic organolithium compounds that exhibit significant configurational stability are relatively rare. 5 A recent review cites several examples of quantitative studies on the inversion dynamics of tertiary benzylic organolithiums where free energy barriers ranging from 9 to 14 kcal/mol at −80 °C were measured. 6 Such low barriers indicate a high degree of configurational instability of benzylic organolithiums (half-life for inversion ≤10 minutes), which provides a challenge to stereoselective synthesis.…”

Reagent-Controlled Lithiation–Borylation

“…This allows the asymmetric synthesis of valuable chiral amines. Aggarwal reported the use of Matteson's amination protocol [37,38] in the asymmetric synthesis of C-tertiary amines in good yield and excellent stereospecificity [39]. This protocol required the initial conversion of the boronic Scheme 14 Total synthesis of (+)-erogorgiaene and its epimers via lithiation-borylationprotodeboronation sequence esters into the corresponding trifluoroborates [40] and their rearrangement with SiCl 4 and an azide.…”