Enantioselective radical C-H amination for the synthesis of β-amino alcohols

Abstract

Asymmetric, radical C-H functionalizations are rare but powerful tools for solving modern synthetic challenges. Specifically, the enantio- and regioselective C-H amination of alcohols to access medicinally valuable chiral β-amino alcohols remains elusive. To solve this challenge, a radical relay chaperone strategy was designed, wherein an alcohol was transiently converted to an imidate radical that underwent intramolecular H-atom transfer (HAT). This regioselective HAT was also rendered enantioselective by harnessing energy transfer catalysis to mediate selective radical generation and interception by a chiral copper catalyst. The successful development of this multi-catalytic, asymmetric, radical C-H amination enabled broad access to chiral β-amino alcohols from a variety of alcohols containing alkyl, allyl, benzyl and propargyl C-H bonds. Mechanistic experiments revealed that triplet energy sensitization of a Cu-bound radical precursor facilitates catalyst-mediated HAT stereoselectivity, enabling the synthesis of several important classes of chiral β-amines by enantioselective, radical C-H amination.

Fig. 1:. Design of a selective, radical C–H amination for the synthesis of β-amino alcohols.

a, Radical C–H amination of cheap and abundant alcohols enables access to the privileged β-amino alcohol architecture – complementing classic approaches that are limited by availability of chiral pool precursors (e.g. amino acids), stoichiometric chiral auxiliaries (e.g. imines), or multi-step manipulation of chiral reagents (e.g. diols). b, Dual challenges for a radical approach include selective formation and trapping of a transient radical intermediate. Specifically, β-regioselectivity is disfavored compared to abstraction of the weaker α C–H bond by an N-centered radical. Moreover, enantioselectivity is both challenging to control and retain in this process, as it may rapidly erode by radical epimerization. c, Proposed mechanism: Alcohol addition to an imidoyl chloride chaperone furnishes an oxime imidate, which binds to a chiral Cu catalyst. This complex then forms an N-centered radical via selective, triplet sensitization by an excited Ir photocatalyst. Regio- and enantio-selective HAT, followed by stereoselective amination, affords a chiral oxazoline. Hydrolysis yields the enantioenriched β-amino alcohol. d, Development of this asymmetric β-C–H amination required a multi-catalytic strategy, wherein a photocatalyst selectively excites a chiral Cu catalyst complex when it is bound to an imidate-activated alcohol. Mechanistic probes illustrate the necessity of each component in ensuring the efficiency and selectivity of this radical C–H amination.

Fig. 2:. Mechanistic experiments.

a, An energy transfer (EnT) pathway (vs single-electron transfer: SET) is supported by CV and DFT data. Specifically, a less reducing photocatalyst (Ir1 vs Ir2) provides greater efficiency due to a higher triplet energy (E_T) and longer-lived excited state (τ). Triplet sensitizer, xanthone, also affords reactivity – indicating the imidate triplet, which is computed to have a significantly weakened N–O bond, is the source of N-centered radical. b, Photo-quenching experiments illustrate the favorability of Cu catalyst coordination during the triplet sensitization and subsequent N-radical generation. c, Desymmetrization of a secondary alcohol demonstrates the ability of this Cu-bound N-radical to discriminate among H-atoms by enantioselective HAT (5:1 e.r.). High diastereoselectivity (>20:1 d.r.) illuminates the role of Cu radical trapping in further upgrading the high enantioselectivity observed for primary alcohols. d, A significant KIE indicates HAT is the product-determining step. Stereoselectivity of the HAT was further probed with two chiral alcohols. Selectivity and efficiency are highly catalyst-dependent for both (S)-Aleve, which contains a β-stereocenter, as well as an enantioenriched secondary alcohol. e, A highly regioselective 1,5-HAT (>20:1 β) outcompetes 1,6-HAT even when much weaker γ-C–H bonds are present. f, Radical clocks indicate radical trapping by Cu is more rapid than allyl radical isomerization, but slower than cyclopropyl ring-opening.

Fig. 3.. Synthetic applications.

a, The enantioenriched oxazoline intermediate is rapidly converted to a family of valuable, chiral products, including amino acids and β-amines, by acidic hydrolysis, oxidation, reduction, or halide substitution. Reagents, yield, and enantiospecificity (e.s.) provided below each example, and full details in SI section VII. Alternatively, directed lithiation and phosphinylation may afford access to PHOX ligands. b, Double C–H amination of a diol affords a new class of chiral catalysts.