Synthesis of 1-Azaspiro[4.4]nonane Derivatives Enabled by Domino Radical Bicyclization Involving Formation and Capture of Alkoxyaminyl Radicals

Abstract

The application of a domino radical bicyclization for the synthesis of compounds containing the 1-azaspiro[4.4]nonane skeleton in 11–67% yields as a mixture of diastereomers is described (trans configuration preference). This process involved formation and capture of alkoxyaminyl radicals. For this purpose, O-benzyl oxime ethers with a brominated or iodinated aromatic ring or a terminal alkynyl group and an alkenyl moiety were employed as starting materials. The bicyclization was initiated by 2,2′-azobisisobutyronitrile or triethylborane and promoted by Bu3SnH. The best results were obtained with O-benzyl oxime ethers containing an alkenyl moiety tethered to electron withdrawing groups or aryl substituents, whereas oxime radical precursor attached to methyl-substituted olefin precluded the capture of alkoxyaminyl radical, giving rise mainly to monocyclized product.

Experimental and theoretical study of the mechanism and rate constants of the sequential 5-exo-trig spirocyclization involving vinyl, aryl and N-alkoxyaminyl radicals

“…Under the same reaction conditions, compound 5c led to the formation of the stereoisomeric mixture of azaspirononane 6c (82%) and the reduced compound 7c (18%), according to nuclear magnetic resonance (NMR) analysis of the crude mixture, which was in agreement with a previous report. 25 Based on the above results and other studies 24,25 it is established that the sequential double cyclization proceeds through a radical chain transfer. Initially, tributylstanyl radicals abstract bromine from oxime ethers 15 and 5c generating the vinyl radical 18a and the aryl radical 18b that compete in two reaction pathways as follows.…”

“…In order to determine the 5-exo cyclization constant of aryl radicals onto oxime ethers via competition experiments, compound 5c reported by Jaramillo-Gómez et al 25 was synthesized, and for the 5-exo cyclization constant of vinyl radicals, a new system containing a vinyl bromide (15) was synthetized using a similar protocol starting from ethyl acetoacetate 9, which was initially alkylated with (E)-(3-bromoprop-1-en-1-yl)benzene (cinnamyl bromide) 10 through a dianion intermediary that generated the β-ketoester 11 that in a second stage was alkylated on the activated methylene with 1,3-dibromoprop-1-ene 12 to produce the oxo-ester brominated 13. Subsequently a dealkoxycarbonylation process, 38 generated the brominated ketone 14, which finally was condensed with O-benzyl hydroxylamine hydrochloride producing (6E)-1-(2-bromophenyl)-7-phenylhept-6-en-3-one O-benzyl oxime 15 as a mixture of isomers E/Z (Scheme 3).…”

“…To get better understanding of the nucleophilicity of the N-alkoxyaminyl radical and taking into account the results of Jaramillo-Gómez et al, 24,25 where the N-alkoxyaminyl radical was successfully added in 5-exo-trig mode onto substituted CvC double bonds, the reactivity of the carbon atoms of the double bond (C 18 and C 20 ) that capture the N-alkoxyaminyl radical was studied. Specifically, the Fukui local reactivity index for the attack of nucleophilic species ( f k + ) was calculated for systems 19a,c-g (Fig.…”

“…This process produced heterocyclic compounds 2 exhibiting a pyrrolidine nucleus fused to an indene backbone, along with compounds 3 and 4 that arose from 1,5-hydrogen transfer followed by double bond isomerization, and 6-exo-trig cyclization, respectively. 24 Recently Jaramillo-Gómez et al 25 reported the synthesis of 1-azaspiro [4.4]nonane type compounds 6 with yields between 11% and 66% by a domino transformation using O-benzyl oxime ethers 5, AIBN or Et 3 B as initiators and Bu 3 SnH as chain transfer (Scheme 2). This process implied the generation and subsequent intramolecular capture of N-alkoxyaminyl radicals by double bonds.…”

Microbial Lipases and Their Potential in the Production of Pharmaceutical Building Blocks

“…[ 86 ], respectively. These compounds were resolved in a biphasic system of diisopyopyl ether/phosphate buffer and are related to homoharringtonine, a molecule approved for the treatment of chronic myeloid leukemia and in the production of antibiotics [ 86 , 87 ].…”