Stereocontrolled 1,3-nitrogen migration to access chiral α-amino acids

Abstract

α-Amino acids are essential for life as building blocks of proteins and components of diverse natural molecules. In both industry and academia, the incorporation of unnatural amino acids is often desirable for modulating chemical, physical, and pharmaceutical properties. We here report a protocol for the economical and practical synthesis of optically active α-amino acids based on an unprecedented stereocontrolled 1,3-nitrogen shift. Our method employs abundant and easily accessible carboxylic acids as starting materials, which are first connected to a nitrogenation reagent, followed by a highly regio- and enantioselective ruthenium- or iron-catalyzed C( sp 3 )−H amination. This straightforward method displays a very broad scope, providing rapid access to optically active α-amino acids with aryl, allyl, propargyl, and alkyl side chains, and also permits stereocontrolled late-stage amination of carboxylic acid-containing drugs and natural products.

Nitrene‐Mediated C−H Oxygenation: Catalytic Enantioselective Formation of Five‐Membered Cyclic Organic Carbonates

“…Interestingly, the isomerized cyclic carbonate ( E )‐ 25 forms almost as a racemate which suggests that it is the C−H abstraction step rather than the C−O bond formation that is the stereodetermining step. This is consistent with other C−H functionalization reactions reported using this class of chiral‐at‐ruthenium catalysts in which we determined that the C−H abstraction is the stereodetermining step [11] . A kinetic isotope effect (KIE) of 5.9 determined from relative rates of the non‐deuterated and deuterated substrates 1 a and 1 a′ , respectively, reveals that the C−H activation is the rate limiting step in the catalytic cycle (Figure 4c).…”

“…This is consistent with other CÀ H functionalization reactions reported using this class of chiral-at-ruthenium catalysts in which we determined that the CÀ H abstraction is the stereodetermining step. [11] A kinetic isotope effect (KIE) of 5.9 determined from relative rates of the non-deuterated and deuterated substrates 1 a and 1 a', respectively, reveals that the CÀ H activation is the rate limiting step in the catalytic cycle (Figure 4c). A Hammett plot with substituents (X) in the para-position of the phenyl moiety of substrate 2 afforded a linear correlation between log(k X /k H ) and the Hammett constants (σ p ) with a negative slope of À 0.17, which is consistent with the proposed 1,7-HAT from a slightly electrophilic ruthenium nitrene intermediate (I), thus favoring electron rich CÀ H bonds (Figure 4d).…”

“…We commenced our study by converting 2‐phenylethanol to the Troc‐protected azanyl carbonate 1 a in a single step (see Supporting Information for details). We were encouraged by recent work in our lab on the use of related azanyl esters as precursors for the formation of α‐amino acids via C−H amination of intermediate transition metal nitrenes [11] . We speculated that in contrast to azanyl esters, the related azanyl carbonates might undergo C−H oxygenation instead of C−H amination, due to an unfavorable 7‐membered transition state for the C−N formation step.…”

“…We were encouraged by recent work in our lab on the use of related azanyl esters as precursors for the formation of α-amino acids via CÀ H amination of intermediate transition metal nitrenes. [11] We speculated that in contrast to azanyl esters, the related azanyl carbonates might undergo CÀ H oxygenation instead of CÀ H amination, due to an unfavorable 7-membered transition state for the CÀ N formation step. Indeed, reaction of azanyl carbonate 1 a with chiral-at-ruthenium catalyst Λ-Ru1 [12] (2 mol %) in methylene chloride in the presence of the base K 2 CO 3 (3.0 equiv) provided the desired cyclic carbonate (R)-2 a in encouraging 38 % yield with 88 % ee, along with smaller amounts of 2-phenylethanol (PE, 11 %) (Table 1, entry 1).…”

Csp2–H Amination Reactions Mediated by Metastable Pseudo-OhMasked Aryl-CoIII-nitrene Species

“…Indeed, Co III masked nitrene species have been crystallographically isolated very recently, further supporting the validity of our study. Moreover, the occurrence of other transition metal masked nitrene species (Ru) is also proposed in chiral α-amino acid synthesis using carbamate derivatives . Interestingly, this in situ masking strategy is a straightforward alternative to the use of stabilized nitrene sources such as dioxazolones (CO 2 -evolving reagent), which focus the scope on amidation reactions. − …”