Amino Acid-Derived trans-N-Chloroformylimidazolidinones: Scalable, Stereoselective Synthesis, Structure, and Utility

Abstract

N-Acyl imidazolidinones, which are key intermediates in the stereoselective synthesis of amino acids by 'self-regeneration of stereochemistry' methods, are classically made by only moderately diastereoselective methods. We now report that cyclisation of pivaldimino-amides with phosgene in the presence of pyridine may be made fully diastereoselective for the trans-N-chloroformylimidazolidinones, and we detail the conformational features of the products. We show that despite the presence of the electrophilic carbamoyl chloride function, the products show remarkable stability, and may be deprotonated to form enolates with useful reactivity for the synthesis of amino acid derivatives. toluene -60 40 95:5 2 toluene -100 20 57:43 3 CH2Cl2 -rt 48 96:4 4 THF -rt 70 91:9

Cu-catalyzed N-3-Arylation of Hydantoins Using Diaryliodonium Salts

“…It is encountered in several drugs, such as nilutamide, sorbinil, and nitrofurantoin, and constitutes a key molecular component of various agrochemicals . The nucleus also has synthetic versatility, for example, in the preparation of amino acids . Of particular interest are N -arylated hydantoins due to their important biological applications (Figure ).…”

‘Reverse biomimetic’ synthesis of l-arogenate and its stabilized analogues from l-tyrosine

“…1a ) that was formed cleanly by hydrogenolysis of 5 in THF. These conditions preserved the (surprisingly stable 15,16 ) carbamoyl chloride group. 17…”

“…1a) that was formed cleanly by hydrogenolysis of 5 in THF. These conditions preserved the (surprisingly stable 15,16 ) carbamoyl chloride group. 17 We found that heating 6 to 60 C for 72 h in the presence of Et 3 N and KI induced dearomatizing spirocyclisation to the dienone 7, a compound with clear structural homology to arogenate 1, in 82% yield.…”

“…The trans diastereoisomer of carbamoyl chloride 5 was synthesised selectively from O-benzyl L-tyrosine methyl ester 2 by formation of the methyl amide 3, condensation with pivalaldehyde, and phosgene-induced cyclization of the imine 4 under kinetic control. 14,15 Heating benzyl ether 5 induces cyclization to an isoquinolinone ring, 13 but quite different reactivity is observed with the free phenol 6 (X-ray crystal structure, conrming relative stereochemistry, shown in Fig. 1a) that was formed cleanly by hydrogenolysis of 5 in THF.…”

An Aliphatic Bischler–Napieralski Reaction: Dihydropyridones by Cyclocarbonylation of 3-Allylimidazolidin-4-ones

“…11 We recently reported a synthesis of the benzo-fused analogues of 3,4-dihydropyridin-2-onesnamely, 3,4-dihydroisoquinolinonesby an unusual version of the Bischler−Napieralski cyclization entailing the intramolecular KI-promoted Friedel−Crafts acylation of Nchloroformylimidazolidinones (see Scheme 1). 12 The starting materials for these reactions, imidazolidinone-derived carbamoyl chlorides carrying a 3-benzyl substituent, were formed diastereoselectively either directly from aromatic amino acids (for example, L-Phe) 12 or by stereoselective benzylation 13 of the stable enolates 14 of their N-chloroformyl substituted precursors. 15 We now show that 3,4-dihydropyridin-2-ones may likewise be formed by an intramolecular Friedel−Crafts reaction, from imidazolidinones bearing 3-allyl substituents.…”