Benzyl N‐[(Benzyloxy)methyl]carbamate: An Improved Aminomethylation Electrophile for the Synthesis of (Benzyloxy)carbonyl (Cbz)‐Protected Chiral β²‐Amino Acids

Abstract

a-Aminomethylation of (R)-DIOZ-alkylated (DIOZ ¼ 4-isopropyl-5,5-diphenyloxazolidin-2-one) substrates is a key step in the asymmetric synthesis of b 2 -amino acids, but it is unfortunately often accompanied by formation of transcarbamation by-products. Aminomethylation was tested using a range of electrophiles, and the amount of by-product formation was assessed in each case. Benzyl N-[(benzyloxy)methyl]carbamate electrophile 3d is unable to form this by-product due to its inherent benzyl substitution. Use of electrophile 3d showed an improved impurity profile in aminomethylation, thus leading to easier intermediate purification.

Structure‐Based Evolution of Subtype‐Selective Neurotensin Receptor Ligands

“…N‐Acylation of the oxazolidinone moiety was achieved with silyl‐protected 3‐(4‐hydroxyphenyl)propionic acid 7 by the mixed anhydride method affording 8 a/b in 80–99 % yield (see Scheme ). Next, amidomethylation of the Ti‐enolate of acyl‐DIOZ‐derivatives 8 was carried out using benzyl N ‐[(benzyloxy)methyl]carbamate as an electrophile and proceeded with 53–67 % yield and 95 % diastereoselectivity, as determined by 1 H NMR spectroscopy. After removal of the O ‐silyl protection by treatment with TBAF, the resulting free phenolic hydroxyl group was protected with a tert ‐butyl substituent, which is necessary for solid‐phase peptide synthesis (SPPS), to afford the corresponding tert ‐butoxy‐derivatives 11 a / b in 47–51 % yield over two steps.…”

Synthetic Story of a Blockbuster Drug: Reboxetine, a Potent Selective Norepinephrine Reuptake Inhibitor

“…For protection of the alcohol, contributing to excellent yield and selectivity, it is recommended to investigate triethylsilyl (TES) ether-, methoxypropyl (MOP) acetal-, triisopropylsilyl (TIPS) ether-, and TBDMS-mediated protection protocols. − Furthermore, enzyme-catalyzed protection of the 1° alcohol is recommended, as it shows tremendous selectivity at room temperature, thus circumventing cryogenic TMS protection conditions. For amine protection, investigation of benzyloxy carbamate (CBz)-, 4-methoxybenzenesulfonamide-, and trifluoroacetamide-based protection protocols are suggested. − In the Mitsunobu reaction, to avoid the formation of so much chemical waste and simplify the separation of the product, numerous modifications to the original reagent combination have been established . Investigation of modified Mitsunobu reaction conditions for reboxetine synthesis is highly recommended.…”