Hydrogen‐Borrowing Alkylation of 1,2‐Amino Alcohols in the Synthesis of Enantioenriched γ‐Aminobutyric Acids

Abstract

For the first time we have been able to employ enantiopure 1,2-amino alcohols derived from abundant amino acids in CÀC bond-forming hydrogen-borrowing alkylation reactions. These reactions are facilitated by the use of the aryl ketone Ph*COMe. Racemisation of the amine stereocentre during alkylation can be prevented by the use of substoichiometric base and protection of the nitrogen with a sterically hindered triphenylmethane (trityl) or benzyl group. The Ph* and trityl groups are readily cleaved in one pot to give gaminobutyric acid (GABA) products as their HCl salts without further purification. Both steps may be performed in sequence without isolation of the hydrogen-borrowing intermediate, removing the need for column chromatography. Scheme 1. A) Previous work, B) proposed hydrogen-borrowing reaction of 1,2-amino alcohols with Ph* methyl ketone.

Recent Advances for Alkylation of Ketones and Secondary Alcohols Using Alcohols in Homogeneous Catalysis

“…In 2021, alkylation of hindered Ph* ketones with enantiopure 1,2‐amino alcohols for the synthesis of enantioenriched γ‐aminobutyric acids was reported by Donohoe and co‐workers (Scheme 9). [16] With [Cp*IrCl 2 ] 2 as catalyst, reactions of Ph* ketones with amino acid‐derived alcohols gave the corresponding products in 32–85% yields with up to 99:1 e.r. It should be noted that the alcohols derived from the glycine, alanine, leucine, and phenylalanine, valine were well tolerated, while the alcohols derived from cysteine, methionine, and glutamine showed no reactivity.…”

Pentamethylphenyl (Ph*) ketones: Unique building blocks for organic synthesis

“…Very recently, we also reported that it is also possible to employ hydrogen borrowing alkylation to prepare enantiopure γ-amino Ph* ketones 44 (Scheme 9B). 16 Initial experiments led to extensive racemization of the sensitive stereogenic centre (α to an aldehyde after oxidation), but racemization could be almost completely suppressed by protecting the nitrogen with a bulky trityl group. Treatment the resulting enantioenriched ketones with acid resulted in both trityl deprotection and Ph* cleavage (vide infra) to release valuable enantiopure γ-amino acids 45.…”

“…8 This chemistry is of great contemporary interest as it provides an environmentally friendly alternative to classical enolate alkylation, enabling α-alkylation to be performed with non-toxic, unactivated alcohols. A generalized process is shown in Scheme 5 in which a ketone (16) undergoes alkylation with an alcohol (15) to generate an alkylated product (17). Such reactions rely upon a transition metal catalyst (M), which initiates the process by oxidizing the alcohol to form the corresponding carbonyl compound (18) along with a metal hydride.…”

Recent advances in C/N-alkylation with alcohols through hydride transfer strategies

“…Recently, Donohoe's group showcased that by employing the [Cp*IrCl 2 ] 2 catalyst combined with NaO t Bu, 1,2-aminoalcohols derived from aminoacids can be transferred to γ-aminobutyric acids with complete enantioenrichment preservation of the amine-bearing stereocentre (Scheme 38). 49 Lower bulk base loading (0.5 eq. NaO t Bu) and assembling a larger protective group (Tr) improved the reaction's stereochemical output.…”