Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki–Heck Reactions

Abstract

Pd(0)-catalyzed Mizoroki-Heck alkenylations and arylations of protected aminocyclopentenes, prepared in a few steps from Vince lactam, afforded functionalized cyclopentenes in high yields and stereoselectivities. DFT calculations were performed to rationalize the high diastereoselectivities. Functionalized cyclopentene products were transformed into valuable chiral building blocks, such as cyclic γ-amino acids and carbocyclic nucleoside precursors.

Stereoselective synthesis and applications of spirocyclic oxindoles

“…150 This strategy was notable for the transdiastereoselectivity observed and the flexibility in increasing the size of the central ring. Larhed and co-workers, in collaboration with AstraZeneca, have built on their previous work on the Heck-Mizoroki reaction to generate functionalised cyclopentenes, 151 to develop an intramolecular variant. Exploiting the selectivity of the Heck-Mizoroki reaction to afford spirocyclopentenes with high diastereocontrol (Scheme 33).…”

Diastereoselective 1,4-Conjugate Addition of Alkyl Cuprates to Methyl Cyclopent-1-enecarboxylates

“…This yielded the title compound as a brown oil (162 g, 90% w/w, 84% overall yield), which was used as such in the next step without further purification. 1 H NMR (500 MHz, DMSO, 90 °C): δ 1.42 (s, 9H); 2.46−2.55 (m, 2H); 2.68 (s, 3H); 2.72−2.80 (m, 2H), 3.69 (s, 3H); 4.79 (tt, J = 9.1, 5.6 Hz, 1H); 6.67−6.72 (m, 1H). 13 C NMR (126 MHz, 90 °C, DMSO): δ 28.6, 29.9, 35.6, 37.…”

“…1 Although this method worked well on a small scale, it suffered from the need for a troublesome protecting group, which required hydroxylamine for its removal, and a nonselective hydrogenation of the double bonds. 1 Moreover, such an approach cannot be applied for introduction of the benzyl side chain to give 1. Thus, we searched for a more general alternative approach where both the benzyl and isobutyl side chains could be introduced efficiently with good diastereoselectivity.…”

Regio- and Stereoselective Synthesis of Spirooxindoles via Mizoroki–Heck Coupling of Aryl Iodides

“…Earlier works reported the selective intermolecular Mizoroki-Heck arylation and vinylation of optically pure aminocyclopentene substrates derived from enantiopure 2azabicyclo[2.2.1]hept-5-en-3-one (Vince lactam). 12,13 A subsequent publication also detailed an intramolecular version of this work, using aryl bromides as precursors in the selective formation of novel spirooxindoles. 14 In continuation of our work in this area, we herein report the reactions of enantiopure cyclopentene-tethered aryl iodides in the intramolecular 5-exo Mizoroki-Heck cyclization to form conformationally restricted and stereopure spirooxindoles in high selectivity.…”

“…Thus, enantiomerically pure (+)-Vince lactam 1, was converted into the corresponding methyl ester 2a as depicted in Scheme 1. 12 The free amine in 2a was next protected as 2,5-dimethylpyrrole, followed by double-bond isomerization to form the more stable 2b (Scheme 1). The protected ester 2b was coupled with a range of iodoanilines in the presence of trimethylaluminium to form amide precursors 3a-j in high yields.…”