Easy preparation of dehydroalanine building blocks equipped with oxazolidin-2-one chiral auxiliaries, and applications to the stereoselective synthesis of substituted tryptophans

Abstract

Chiral dehydroamino acid building blocks are versatile starting materials for the preparation of optically active unusual amino acids and other compounds of pharmacological interest. Herein we disclose the expedient preparation of dehydroalanines (ΔAla) equipped with oxazolidin-2-one (Oxd) chiral auxiliaries, Ts-Oxd-ΔAla-OMe. These compounds have been obtained in high yields from dipeptides Ts-Ser/Thr/phenylSer-Ser-OMe by the one-pot cyclization-elimination reaction with N,N-disuccinimidyl carbonate and catalytic DIPEA. To test the efficacy of the chiral auxiliaries in controlling asymmetric transformations, the Friedel-Crafts alkylations of indoles carrying diverse substituents were performed in the presence of Lewis and Brønsted acids. The reactions proceeded with good to excellent diastereomeric ratios giving (S)- or (R)-tryptophan derivatives, isolated very conveniently by simple flash chromatography. To verify the utility of this approach, optically pure (S)-2-methyltryptophan and (S)-5-fluorotryptophan were obtained and utilized to prepare analogues of endogenous opioid peptide endomorphin-1, H-Tyr-Pro-Trp-PheNH2.

In-Peptide Synthesis of Imidazolidin-2-one Scaffolds, Equippable with Proteinogenic or Taggable/Linkable Side Chains, General Promoters of Unusual Secondary Structures

“…The strategy we adopted is outlined in Scheme . Dipeptides containing ( S )- or ( R )-serine 3 were prepared in solution as described in the literature . The dipeptide esters 3 were isolated in good yield (in the 70–85% range, 80–90% pure according to analytical RP HPLC) by flash chromatography over silica gel.…”

“…Dipeptides containing (S)-or (R)-serine 3 were prepared in solution as described in the literature. 36 The dipeptide esters 3 were isolated in good yield (in the 70−85% range, 80−90% pure according to analytical RP HPLC) by flash chromatography over silica gel. The dipeptides 3 were treated with a mixture of triphenylphosphine, iodine (1.2 equiv each), and imidazole (2.5 equiv), 37 affording β-iodo-Ala-dipeptides 4, not isolated because of intrinsic instability; 37 TLC analyses of the reaction mixtures revealed the complete consumption of 3.…”

“…The reaction was performed under conditions which allow using ( S )- or ( R )-serine esters without protection of the hydroxy group . Briefly, a stirred solution of the N-protected amino acid (0.5 mmol) in 4:1 DCM/DMF (4 mL) was treated with HOBt (0.6 mmol) and 2-(1 H -benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 0.6 mmol) at rt and under inert atmosphere.…”

A Brief Survey on Recent Endomorphin-1 and Endomorphin-2 Analogues

“…The introduction of the nitro group, halogens, alkyl groups, and combinations of different groups into the indole ring of Trp in 20 [74,75], gave the 5-NO 2 -tripeptide (Table 1, 21) and 7-Br-2Me-tripeptide (Table 1, 22) with interesting behavior in vitro and in vivo [24]. The compound 21 showed a significant MOR affinity in vitro, with Ki = 51.9 nM.…”

Conformational preferences and synthesis of isomers Z and E of oxazole‐dehydrophenylalanine

“…αβ‐Didehydro‐α‐amino acids, commonly known as dehydroamino acids (ΔXaa), belong to nonstandard amino acids occurring primarily in natural peptides produced by bacteria and fungi . Dehydroamino acids continuously attract attention in various areas, mainly in synthesis, as designed products or suitable substrates, including asymmetric hydrogenation as well as in the conformational studies . Dehydrophenylalanine (ΔPhe), although scarcely presented in natural compounds, is the most often studied dehydroamino acid .…”