N-Chloroformylimidazolidinone Enolates as 1,3-Dipolar Reagents for the Stereoselective Synthesis of 3,4-Dihydroisoquinolones

Abstract

N-Chloroformyl imidazolidinone derivatives of enantiopure amino acids may be deprotonated to give remarkably well-behaved enolates with both nucleophilic and electrophilic character. The enolates undergo diastereoselective C-alkylation with benzylic halides. A Bischler-Napieralski-like cyclization reaction onto the chloroformyl group, induced by either nucleophilic (KI, 2,6-lutidine) or Lewis acid (AlCl3) catalysis, gives substituted 3,4-dihydroisoquinolone derivatives in enantioenriched form. The reaction sequence constitutes a formal [3+3] route to the 6-membered lactam ring of the dihydroisoquinolones.

‘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 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.…”

Scalable synthesis and coupling of quaternary α-arylated amino acids: α-aryl substituents are tolerated in α-helical peptides

“…Since our original publication, 6 we have optimised the method for diastereoselective formation of trans N -chloroformylimidazolidinones. 7 In this way, 40 g of 2 (R = H) were readily prepared as a single diastereoisomer (our previously reported method gave a mixture of 2 and its cis isomer). Sequential addition of KHMDS to a solution of 2 and 4-bromo- N -methylaniline (the formal equivalent of the aryl electrophile) effected one-pot tandem urea formation and diastereoselective N to C migration of the aryl ring to install the quaternary centre.…”

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

“…Line shape modelling (Figure 1h) gave a correspondingly higher barrier to conversion of the major to the minor rotamer of 71.7 kJ mol -1 at 300 K. The remarkable stability of the carbamoyl chlorides 2 permitted them to be very readily isolated and purified by chromatography on silica, and suggested that despite their electrophilic reactivity it might nonetheless be possible to deprotonate them to form an enolate. 18 In initial investigations, 2a was treated with base at room temperature and quenched with allyl bromide, but only decomposition was noted with LDA, KHMDS or LiHMDS (Table 2, entries 1-3).…”

“…We have recently described several reactions in which the N -chloroformyl derivative of an imidazolidinone plays a pivotal role, − and this work showed that the two diastereoisomers of these carbamoyl chlorides displayed very different reactivities. In one particular family of Bischler–Napieralski-like cyclizations, only the trans isomer was of use.…”