Synthesis of Enantioenriched Tertiary Boronic Esters by the Lithiation/Borylation of Secondary Alkyl Benzoates

Abstract

Simple, secondary 2,4,6-triisopropyl benzoates (TIB esters) and secondary dialkyl N,N-diisopropyl carbamates have been reported to be resistant to deprotonation by strong bases. We have found that the combination of sBuLi (1.6 equiv) and TMEDA (6 equiv) in CPME at -60 °C enables deprotonation of unactivated secondary dialkyl TIB esters, but not the carbamates. These carbanions were reacted with a range of neopentyl boronic esters which, after 1,2-metalate rearrangement and oxidation, gave a range of tertiary alcohols in high yield and universally high er. Further functional group transformations of the tertiary boronic esters were demonstrated (conversion to quaternary centers, C-tertiary amines) together with application of the methodology to the synthesis of the simplest unbranched hydrocarbon bearing a quaternary center, (R)-4-ethyl-4-methyloctane, validating the synthetic utility of the methodology.

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.…”

Selective uni- and bidirectional homologation of diborylmethane

“…The transformation of secondary alkyl benzoates ( i.e. non-benzylic) 22 necessitated the generation of the chiral carbenoid from the corresponding stannane through tin–lithium exchange. The carbenoid so generated from 19 (>99 : 1 e.r.)…”

Reagent-Controlled Lithiation–Borylation

“…Without acidifying groups it had been reported such substrates could not be deprotonated [50,51] and therefore could not be used in lithiation-borylation processes. This major limitation was recently addressed by Aggarwal who demonstrated that the combination of using TIB esters together with CPME as solvent enabled deprotonation of dialkyl benzoates [52]. Subsequent reaction with neopentyl boronic esters and 1,2-metallate rearrangement gave the homologated boronic esters which were oxidized to give the chiral carbinols in good yield and perfect stereospecificity ( Table 9).…”

“…In this case the enantioenriched TIB ester 85 underwent lithiation-borylation with n-Bu-B(neo) to give the boronic ester 86 in moderate yield but excellent stereospecificity. Zweifel olefination [18] and hydrogenation installed the ethyl group and completed the synthesis of 84 in just four steps [52]. The lithiation-borylation is not restricted to the use of lithiated carbamates and benzoates.…”