Full Chirality Transfer in the Conversion of Secondary Alcohols into Tertiary Boronic Esters and Alcohols Using Lithiation–Borylation Reactions

Abstract

Dedicated to Professor Saverio Florio on the occasion of his 70th birthdayA general method for the preparation of fully substituted carbon atoms (e.g. quaternary stereogenic centers [1] or tertiary alcohols [2] ) that routinely gives high enantioselectivities (> 96 % ee) with broad substrate scope is one of the most challenging goals in organic synthesis.[3] Our research group has recently described a conceptually new method that comes close to meeting such a challenge (Scheme 1).[4] In this process, readily available enantioenriched secondary alcohols were first converted into carbamate compounds. Lithiation and subsequent reaction with boron reagents gave, after oxidative workup, tertiary alcohols with high ee values. Perhaps the most intriguing facet of this novel methodology was that in all cases the reactions occurred with essentially complete inversion of configuration when boranes were employed but almost complete retention of configuration when boronic esters were used. Although the reaction worked well for simple substrates (> 90 % ee), we have found that the introduction of sterically more demanding groups in the carbamate or boronic ester or the introduction of electronwithdrawing aromatic groups in the carbamate resulted in a considerable erosion of enantioselectivity. Herein, we provide a rationale for the observed decrease in enantioselectivity and through understanding the intricacies of the process, we also present a solution to the problem that now results in > 98 % ee for all the substrates tested, even the most demanding.The problem we encountered is illustrated in Scheme 2 (and expanded in the Supporting Information). Thus, reaction of the para-chlorophenyl-substituted carbamate 1 c with EtBpin 2 b (1.1 equiv) gave the tertiary boronic ester with only 40 % ee. Furthermore, we observed an unusual dependence of the ee value on the stoichiometry: increasing the stoichiometry of 2 b from 1.1 equivalents to 3 equivalents led to an increase in the ee value of the product 4 cb from 40 % to 96 % ee.Although a number of possible explanations can be advanced for this observation, we focused on the possible scenario shown in Scheme 3. We suspected that the critical issue was not the selectivity in the formation of the atecomplex, for which it would be difficult to rationalize the dependence of the ee value on stoichiometry, but instead the fate of the ate-complex upon warming. Even though the desired stereospecific 1,2-migration occurred upon warming, it was also possible that competing dissociation of the atecomplex (k À1 ) back to the starting lithiated carbamate and boronic ester species might also take place.[5] This dissociation could be followed by racemization of the lithiated carbamate and subsequent erosion of the ee value. The dependence of the ee value on the stoichiometry can therefore be understood. At low stoichiometry, reversion to starting materials results in a low concentration of the boronic ester, and so the subsequent recombination of the lithiated carbamate with RBpin is inevitably ...

Enantiospecific sp2–sp3 coupling of secondary and tertiary boronic esters

“…We therefore tested enantioenriched, benzylic 40,41 and non-benzylic 42 tertiary boronic esters 1k-n in our process ( Table 2) and found that the desired products 2k-n were obtained in good yields and complete stereospecificity, demonstrating the power of the new methodology. As these boronic esters were readily prepared in essentially enantiopure form, the furyl-coupled products were also obtained in similarly enantiopure form as well.…”

“…A range of enantioenriched secondary 39 and tertiary boronic esters [40][41][42] were then prepared by lithiation-borylation methodology or by hydroboration ( Figure 2, see SI for details) and subsequently tested under these optimized reaction conditions (Table 1). Figure 2.…”

Aufbau von asymmetrischen quartären Kohlenstoffzentren mit hoher Enantioselektivität

“…[3] Zuvor war ihnen durch Homologisierung eines Boratkomplexes die hoch enantioselektive Synthese von tertAlkylboronaten aus den Carbamaten 1 gelungen, die sich von leicht zugänglichen, optisch aktiven sekundären Alkohlen ableiten. [4] Nach der Synthese der enantiomerenreinen Verbindungen 3 untersuchten Aggarwal et al die Matteson-Homologisierung, [5] die Vinylierung nach Zweifel et al [6] und die DreiKohlenstoff-Homologisierung nach Brown et al [7] (Schema 2).…”

“…Beim derzeitigen Stand ist eine Arylgruppe am stereogenen Kohlenstoffatom allerdings unvermeidlich, da 3 durch Homologisierung aus 1 hergestellt wird. [4] Alternativ dazu wurden von Hoveyda et al kürzlich kupferkatalysierte asymmetrische Boryl-Additions-und -Substitutionsreaktionen mit a,b-ungesättigten (Thio)estern und Allylcarbonaten durchgeführt. Diese Reaktionen führten nicht nur zu Boronaten wie 3, sondern auch mit hoher Enantioselektivität zu den nichtarylierten Boronaten 12 und 13 (Schema 5).…”

“…[3] Zuvor war ihnen durch Homologisierung eines Boratkomplexes die hoch enantioselektive Synthese von tert-Alkylboronaten aus den Carbamaten 1 gelungen, die sich von leicht zugänglichen, optisch aktiven sekundären Alkohlen ableiten. [4] Nach der Synthese der enantiomerenreinen Verbindungen 3 untersuchten Aggarwal et al die Matteson-Homologisierung, [5] die Vinylierung nach Zweifel et al [6] und die Drei-Kohlenstoff-Homologisierung nach Brown et al [7] (Schema 2 [4] Alternativ dazu wurden von Hoveyda et al kürzlich kupferkatalysierte asymmetrische Boryl-Additions-und -Substitutionsreaktionen mit a,b-ungesättigten (Thio)estern und Allylcarbonaten durchgeführt. Diese Reaktionen führten nicht nur zu Boronaten wie 3, sondern auch mit hoher Enantioselektivität zu den nichtarylierten Boronaten 12 und 13 (Schema 5).…”