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 ...

Regio‐ and Stereoselective Homologation of 1,2‐Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3‐Diols and Sch 725674

“…Suspecting that this product was only generated while the reaction mixture was being warmed from À78 8 8Ctoroom temperature,weperformed an experiment using excess carbamate and where MeOH was added to the reaction mixture immediately prior to warming, thus protonating any remaining lithiated carbamate. [11] Pleasingly,t he use of this methanol-quench protocol, for both the carbamate and the benzoate,gave agood yield of 3 and only trace amounts of the double-addition product (Scheme 2a, entries 3and 5), thus supporting our hypothesis and completing as uite of conditions for the regio-and stereoselective homologation of 1,2-bis(boronic esters).…”

“…95:5, which is in line with the levels of enantioselectivity we often obtain for sparteine-mediated deprotonation of primary triisopropyl-benzoates. [11] Ther eaction was selective for transformation of the primary boronic ester;w ed id not observe any products arising from homologation of the secondary boronic ester or homologation of both boronic esters.T he remaining benzoate ester was then reacted with pentyl boronic ester 23 in another lithiation-borylationoxidation to give tris(tert-butylsilyl)-protected tetraol 29, which was isolated in 85 %y ield as a9 0:5:5m ixture of diastereomers.T he diastereopurity of 29 again is in line with the expected reagent-controlled % 95:5 selectivity in the sparteine-mediated deprotonation of 28,i mposed on a9 5:5 mixture of diastereomers of 28.This reaction was scaled up to provide grams of material (2.0 g). Thet erminal alkene was then converted into the a,b-unsaturated methyl ester through ruthenium-catalyzed cross-metathesis with methyl acrylate.…”

Reagent-Controlled Lithiation–Borylation

“…This dissociation-racemization pathway could be eliminated by (1) esters or (2) using less hindered neopentyl boronic esters in place of pinacol boronic esters (Table 6) [30].…”

Asymmetric Synthesis of Secondary and Tertiary Boronic Esters

“…Further studies established protocols to obtain tertiary boronic esters across ar ange of substrates in excellent levels of stereocontrol. [183][184][185][186][187] This methodology has also found significant success in the synthesis of natural products and its amenability to iteration…”