Enantiospecific Solvolytic Functionalization of Bromochlorides

Abstract

Herein, we report that under mild solvolytic conditions, enantioenriched bromochlorides can be ionized, stereospecifically cyclized to an array of complex bromocyclic scaffolds, or intermolecularly trapped by exogenous nucleophiles. Mechanistic investigations support an ionic mechanism wherein the bromochloride serves as an enantioenriched bromonium surrogate. Several natural product-relevant motifs are accessed in enantioenriched form for the first time with high levels of stereocontrol, and this technology is applied to the scalable synthesis of a polycyclic brominated natural product. Arrays of nucleophiles including olefins, alkynes, heterocycles, and epoxides are competent traps in the bromonium-induced cyclizations, leading to the formation of enantioenriched mono-, bi-, and tricyclic products. This strategy is further amenable to intermolecular coupling between cinnamyl bromochlorides and a diverse set of commercially available nucleophiles. Collectively, this work demonstrates that enantioenriched bromonium chlorides are configurationally stable under solvolytic conditions in the presence of a variety of functional groups.

Figure 1

(A) Representative bromocyclic natural products. (B) Putative biosynthetic pathway for the biosynthesis of two related natural products involving several discrete bromocyclization steps. (C) Our previous work on a stereospecific bromopolyene cyclization and that accomplished in this report.

Figure 2

Computational investigation of the interconversion of bromochloride constitutional isomers at the M06-2X/6-31G+(d) level of theory; uncorrected electronic energies are listed in kcal/mol (PCM = polarizable continuum model).

Scheme 1

Solvolytic epoxide opening cascade for the synthesis of a brominated pyran^{a a}Reagents and conditions: (i) K₂CO₃ (1.5 equiv), 1,1,1,3,3,3-hexafluoroisopropanol (0.05 M), rt; (ii) HCl (concentrated aq., 5 equiv), wet Et₂O, rt, 34% over two steps.

Scheme 2

Application of the dihalide solvolysis to a scalable, enantioselective synthesis of a brominated natural product^{a a}Reagents and conditions: (a) K₂CO₃ (1.5 equiv), 1,1,1,3,3,3-hexafluoroisopropanol (0.05 M), rt; (b) trifluoroacetic acid, CH₂Cl₂, rt; PhMe, 110 °C, 75% over two steps; (c) trimethylaluminum (3.0 equiv), N,O-dimethylhydroxylamine hydrochloride (3.0 equiv), CH₂Cl₂, 0 °C to rt; (d) methyllithium lithium bromide complex (3.5 equiv), THF, −78 °C; (e) vinylmagnesium chloride, Et₂O, 0 °C, 73% over two steps; (f) BF₃· OEt₂ (1.5 equiv), CH₂Cl₂, 4 °C, 50% (6:1 dr).