Synthesis of 3-borylated cyclobutanols from epihalohydrins or epoxy alcohol derivatives

Abstract

There is an increasing interest in cyclobutanes within the medicinal chemistry community. Therefore, methods to prepare cyclobutanes that contain synthetic handles for further elaboration are of interest. Herein, we report...

Synthesis of Borylated (Aminomethyl)cyclopropanes Using C1–Bisnucleophiles

“…3a Along these lines, our group recently reported an approach to synthesize poly substituted borylated cyclobutanols from epihalohydrins and epoxy alcohol derivatives enabled by two sequential C−C bond forming reactions (Scheme 1b, left). 8 Based on the established reactivity of lithiated 1,1diborylalkanes with oxygen-based electrophiles, we were interested in exploring the reactivity of these nucleophiles with nitrogen-based electrophiles. When compared to their oxygen-containing analogues, nitrogen-based electrophiles have received significantly less attention, 6a,9 possibly due to weaker coordination between nitrogen and boron.…”

“…Recent efforts have focused on trapping the resulting nucleophilic species with electrophiles, leading to tandem reactions to rapidly build up molecular complexity . Along these lines, our group recently reported an approach to synthesize poly substituted borylated cyclobutanols from epihalohydrins and epoxy alcohol derivatives enabled by two sequential C–C bond forming reactions (Scheme b, left) …”

“…This reaction proceeds through two sequential C−C bond forming steps via a pathway that is divergent from what is observed with epihalohydrins. 8 We initiated our study by exploring the reactivity of αbromoaziridine 2a with lithiated 1,1-diborylalkane [Li]-1a, prepared in situ upon treating 1-phenyl-1,1-diborylmethane (1a) with LDA. Following extensive optimization (see SI for further details), we found that treating bromoaziridine 2a in THF followed by the addition of DMSO was ideal for both reaction yield and diastereoselectivity (Table 1, entry 1).…”

“…exemplifies the divergent reactivity between epibromohydrins and α-bromoaziridines, as no cyclobutylamine product was observed in the 1 H NMR spectrum of the crude reaction mixture. 8 Furthermore, the trans relationship between the Ph and methylamine substituent would be challenging to access using known methods. 10−12 The molar ratio of [Li]-1a can be lowered to 1.0 equiv.…”

Formal γ−C−H Functionalization of Cyclobutyl Ketones: Synthesis of cis‐1,3‐Difunctionalized Cyclobutanes

“…[1,2] Multiple small molecules containing 1,3-disubstituted cyclobutanes have entered the clinic, including PF-03654746, a histamine H 3 antagonist for the treatment of cognitive disorders, [3] and TAK-828F, a retinoic acid-related orphan receptor (RORγt) inverse agonist for the treatment of autoimmune diseases (Figure 1A), [4] highlighting the value of this unique motif in drug design. Accordingly, a variety of synthetic strategies have been developed for accessing 1,3-difunctionalized cyclobutanes, including: (i) intermolecular [2+2] [5] and [3+1] [6] cycloadditions; (ii) strain-release-driven CÀ C cleavage/functionalization of bicyclo [1.1.0]butanes; [7] and (iii) the direct radical CÀ H chlorination of cyclobutanes (Figure 1B). [8] Unfortunately, these strategies typically provide little control over cis-vs. trans-selectivity, and most rely on specialized precursors (activated alkenes, 1,1-diborylalkanes, or bicyclo-[1.1.0]butanes), which can be difficult to access efficiently.…”