Diarylborinic Acid-Catalyzed Regioselective Ring Openings of Epoxy Alcohols with Pyrazoles, Imidazoles, Triazoles, and Other Nitrogen Heterocycles

Abstract

A method for regioselective ring openings of 3,4- and 2,3-epoxy alcohols with ambident nitrogen heterocycles is described. Using a diarylborinic acid catalyst, a single regioisomer is favored in couplings of nucleophile and electrophile partners that display low regioselectivity under conventional conditions. The method provides access to aromatic heterocycles bearing stereochemically defined, functionalized alkyl substituents, a product class similar in structure to medicinally relevant compounds such as the acyclic nucleoside analogues.

Borinic Acid Catalyzed Regioselective N-Alkylation of Azoles

“…Our research group has developed catalytic processes that employ organoboron compounds to influence site selectivity or regioselectivity in several reaction types, including O–H and C–H functionalizations of carbohydrate derivatives and ring-opening reactions of epoxy alcohols. − A new facet of this mode of catalysis emerged in our explorations of the ring openings of 2,3- and 3,4-epoxy alcohols with azole-type heterocycles; in addition to influencing the regioselectivity of epoxide ring opening, favoring attack at the position proximal to the hydroxyl group, the diarylborinic acid catalyst (Ar 2 BOH) also resulted in selective N -functionalization of the ambident nucleophile (Scheme ). This outcome was consistent with a tethering catalysis mechanism involving simultaneous complexation of the nucleophile and electrophile via B–O and B–N bond formation, a proposal supported by computational modeling of ring-opening transition states using density functional theory. We aimed to build on this result by evaluating the utility of arylborinic acids for regioselective N -functionalizations of ambident heterocycles with other electrophile classes, particularly those lacking a hydroxy group for catalyst tethering.…”

“…17 epoxide ring opening, favoring attack at the position proximal to the hydroxyl group, 20 the diarylborinic acid catalyst (Ar 2 BOH) also resulted in selective N-functionalization of the ambident nucleophile (Scheme 2). 21 This outcome was consistent with a tethering catalysis mechanism involving simultaneous complexation of the nucleophile and electrophile via B−O and B−N bond formation, a proposal supported by computational modeling of ring-opening transition states using density functional theory. We aimed to build on this result by evaluating the utility of arylborinic acids for regioselective Nfunctionalizations of ambident heterocycles with other electrophile classes, particularly those lacking a hydroxy group for catalyst tethering.…”

Ring Opening of Epoxides by Pendant Silanols

“… − Nucleophilic opening of epoxides can be broadly characterized as either intermolecular or intramolecular. Intramolecular opening of epoxides by pendant alcohols is a known route to a variety of oxygen heterocycles, including furans, pyrans, and medium-sized rings, , and this strategy has been applied on numerous occasions in natural product synthesis. − Several laboratories have established that “temporary tethering” is an effective strategy for regiocontrol in intermolecular ring-opening reactions of epoxides. − In such reactions, a Lewis acid or organocatalyst noncovalently binds to both the substrate and the nucleophile and templates attack at a single site of the epoxide. In contrast to these two areas, the use of covalent tethers for epoxide opening is much less established, and most explorations have focused on carbonates, − carbamates, − and trichloroacetamidates .…”

Ring Opening of Aziridines by Pendant Silanols Allows for Preparations of (±)-Clavaminol H, (±)-Des-Acetyl-Clavaminol H, (±)-Dihydrosphingosine, and (±)-N-Hexanoyldihydrosphingosine

“… ,, Pioneering efforts on syntheses of vicinal amino alcohols have focused on transition metal catalyzed processes to install both N- and O -moieties in a single transformation. − A complementary approach is the ring opening of epoxides with N -nucleophiles and of aziridines with O -nucleophiles. , This untethered approach − is convenient from the perspective of step counts, but challenges with regiocontrol often result in intractable product mixtures. Temporary tethering using Lewis acid templates affords excellent regiocontrol with epoxides, − but only one such report exists with aziridines . Our laboratory has a programmatic focus on the development of the di- tert -butyl-silanol auxiliary into a uniquely reactive functional handle. − We envisioned a ring opening of aziridines by pendant di- tert -butyl silanol auxiliaries, which would afford protected amino alcohols in a single transformation.…”