Enantioselective, Chromatography-Free Synthesis of β³-Amino Acids with Natural and Unnatural Side Chains

Abstract

β 3 -Amino acids are key components of some pharmaceuticals, excellent surrogates for metabolically labile αamino acids, and building blocks for chiral heterocycles. Unfortunately they are not easily accessible in enantiomerically pure form, especially when possessing unnatural side chains. A flexible, chromatography-free process for the synthesis of enantiopure β 3 -amino acids possessing natural and unnatural side chains is described. The procedure uses inexpensive starting materials and reagents and offers a good alternative to the hazardous and expensive Arndt−Eistert homologation of enantiopure α-amino acids. Its utility has been demonstrated with the preparative scale synthesis of two valuable β 3 -amino acids possessing unnatural side chains.

Intermolecular Aminocarbonylation of Alkenes using Concerted Cycloadditions of Iminoisocyanates

“…The synthesis of β-amino carbonyl compounds from readily available starting materials has attracted considerable attention. , Many successful approaches use naturally abundant α-amino acids as substrates, and many synthetic methodologies involve forming either the C–N or C α –C β bond . The preparation of enantiopure β-amino carbonyl compounds has also stimulated intense research over the last three decades. , Many of these methods are useful if the products are simple and substrates are readily available. However, some strategic disconnections remain underdeveloped for the synthesis of β-amino carbonyl compounds, such as reactions involving C–H activation and the aminocarbonylation of alkenes.…”

“…6 The preparation of enantiopure β-amino carbonyl compounds has also stimulated intense research over the last three decades. 7,8 Many of these methods are useful if the products are simple and substrates are readily available. However, some strategic disconnections remain underdeveloped for the synthesis of βamino carbonyl compounds, such as reactions involving C−H activation and the aminocarbonylation of alkenes.…”

Synthetic fermentation of β-peptide macrocycles by thiadiazole-forming ring-closing reactions

“… 52 An HWE reaction with phosphonate 22 allowed installation of the acetal-protected α-ketoacid framework. 53 , 54 Subsequent conversion to thiohydrazide 24 using Lawesson's reagent, followed by unveiling of the free α-ketoacid via ester hydrolysis afforded initiator 16 .…”

“…The elongation monomers used in this process were synthesized according to previous reports. 48 , 54 Initially, oligomerization using only one elongation monomer was performed, reducing the complexity of the resulting peptide mixtures and simplifying initial analysis. Elongation was carried out as previously described: two equivalents of the monomer were employed to favor formation of peptides containing 2–3 monomer units.…”

Reversal of Stereoselectivity in Cycloadditions of Five‐Membered Cyclic Nitrones Derived from Hexoses

“…[9b] Isomerization of 1,2:5,6‐bis(acetonide) 14 with p ‐toluenesulfonic acid monohydrate (PTSA · H 2 O) in acetone then gave the thermodynamically more stable 2,3:5,6‐di‐ O ‐isopropylidene‐β‐ d ‐gulofuranose ( 10 ) in 83 % yield. Condensation of this compound with hydroxylamine hydrochloride produced oxime 15 in 88 % yield as an inseparable mixture of ( E ) and ( Z ) isomers in a ratio of 60:40 . Compound 15 was then subjected to reaction with tert ‐butyldimethylchlorosilane (TBSCl), and silylated oxime 16 was formed selectively in 99 % yield [( E )/( Z ) ≈ 60:40].…”