Spirocyclopropane Isoxazolidines, Octahydropyrindin-4-ones and β-Lactams with Biomimetic Ethylene Release from the Electrophilic Substitution of a 1,1-Ethyleneallylzinc Complex

Abstract

Electrophilic substitution of 1-ethenylcyclopropyl mesylate by 3,3-diethoxypropanal in the presence of palladium(0) (5%) and diethylzinc (2 equivalents) provided 5-cyclopropylidene-1,1-diethoxy-3-hydroxypentane; its nitrone derivatives underwent intramolecular cycloaddition to provide spirocyclopropane isoxazolidines, which then were transformed under thermal or acidic conditions, into octahydropyrindin-4-ones or bicyclic b-lactams with the ethylene phytohormone extrusion, respectively. Use of chiral auxiliaries, i.e, (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles.It is a matter of common knowledge now, that the cyclopropane ring, which can selectively undergo either ring opening, or ring enlargement or cycloaddition reactions, provides building blocks of unprecedented synthetic potential. 1 It is also known that, when substituted by simple functionalities, natural or synthetic three-membered rings are endowed with a large spectrum of biological activities, allowing consequently the design of new drugs. 2 We have recently reported the ready asymmetric synthesis of cis-fused tricyclic isoxazolidines exo-2 involving regioselective nucleophilic substitution of p-1,1-ethyleneallylpalladium complex 1 by optically active a-amino acids, followed by diastereoselective 1,3-dipolar cycloaddition of the derived nitrones. Subsequently, the spirocyclopropane isoxazolidines exo-2 have been shown to undergo either thermally induced ring expansion into the pyrrolo[3,4-b]pyridin-4-ones 3, 3-5 or acid induced ring contraction into the b-lactams 4 with concomitant extrusion of ethylene (Scheme 1). 6In order to widen the scope of this new approach towards these biologically important compounds, we have now investigated an alternative access to spirocyclopropane isoxazolidines such as 2 based on the electrophilic substitution of 1,1-ethyleneallylzinc complexes.We have observed that, in the presence of diethylzinc in THF, the p-1,1-ethyleneallylpalladium complex 1, arising from the readily available 1-ethenylcyclopropylsulfonates 5a,b and palladium(0), 7,8,10 underwent through the formation of s-or p-1,1-dimethyleneallylzinc complexes 6, chemo-and regioselective electrophilic addition of aldehydes and ketones. 9 Effectively, substitution of mesylate 5a by 3,3-diethoxypropionaldehyde 7 11 performed in the presence of 5% of palladium(0) [from Pd(OAc) 2 and 2 PPh 3 ] and two equivalents of diethylzinc in THF at room temperature for 3 h, provided 5-cyclopropylidene-1,1-diethoxy-3-hydroxypentane 8, in 63% yield after chromatography (Scheme 2). Scheme 2O-protection (Ac 2 O, DMAP) of the secondary allylic alcohol 8 and subsequent deacetalisation under acidic conditions (0.2 M H 2 SO 4 , THF) led to the 3-acetoxy-5-cyclopropylidenepentanal 9a (R = Ac) in 72% overall yield. This aldehyde reacted at room temperature with N-methylhydroxylamine hydrochloride in the presence of one equivalent of pyridine in diethyl ether at 0°C to give the corresponding N-methylnitrone 10a which, spontaneously, evolved to a 1:1 mixture of ...

The Chemistry of Cyclopropanols

“…Nucleophilic displacement of the hydroxyl group in less active cyclopropanol derivatives may be successfully realized by activation of the leaving group. Thus, Salaün and co-workers found that 1-alkenyl cyclopropyl esters readily form π- or σ-1,1-ethyleneallylmetal complexes which afford cyclopropane derivatives. ,,,,− Formation of allylmetal complexes 115 proceeded readily when the corresponding sulfonic esters 116 (mesylates or tosylates) were treated with catalytic amounts of palladium(0) species at room temperature. The former underwent regio- and diastereoselective substitution reactions to provide alkylidenecyclopropanes 117 or (1-alkenyl)cyclopropanes 118 (Scheme ).…”

π-1,1-Dimethyleneallylmetal and Homologous Complexes: Their Application in Organic Synthesis

“…O -Protection and acidic deacetalisation led to the pentanal 265a (R‘ = Ac) in 72% overall yield. Addition of N -methylhydroxylamine hydrochloride gave the corresponding N -methylnitrone 266a , which spontaneously envolved to a 50:50 mixture of fused exo -isoxazolidine 267a (32%) and of its diastereomer endo - 268a (32%) (Scheme ) 78 …”

“…Separated by flash chromatography, the pure cycloadduct exo - 267a underwent on heating in xylenes(126−140 °C), ring expansion with formation in 75% yield of the pyridinone exo - 269a (Scheme ) …”

“…Otherwise, O - protection of 264 by (2 S )-acetyllactyl chloride ( n -BuLi, 1 equiv) followed by deacetalisation (HCOOH) gave in 73% yield the cyclopropylidenepentanal 265b [R = (2 S )-acetyllactyl]. Following the same procedure, addition of MeNHOH and spontaneous rearrangement of the resulting nitrone 266b gave again a 50:50 diastereomeric mixture of fused isoxazolidines exo - 267b (26%) and endo - 268b (26%) (Scheme ) . Separated by chromatography pure exo - 267b underwent likewise ring expansion on heating in xylenes at reflux, to provide in 74% yield the enantiomerically enriched octahydropyridin-4-one exo - 269b (Scheme ) .…”

“…Following the same procedure, addition of MeNHOH and spontaneous rearrangement of the resulting nitrone 266b gave again a 50:50 diastereomeric mixture of fused isoxazolidines exo - 267b (26%) and endo - 268b (26%) (Scheme ) . Separated by chromatography pure exo - 267b underwent likewise ring expansion on heating in xylenes at reflux, to provide in 74% yield the enantiomerically enriched octahydropyridin-4-one exo - 269b (Scheme ) . Cleavage of the acetoxy protective group of exo - 269a and of the chiral auxiliary group of exo - 269b were achieved with quantitative yields under basic conditions (K 2 CO 3 , MeOH) …”