Synthesis of enantiomeric β-amino ketones via 1,3-dipolar cycloaddition and chromatographic resolution

Abstract

. 72, 1347 (1994). The cycloaddition reactions of 3,4,5,6-tetrahydropyridine I-oxide 1 with the homochiral alkynyl sulfoxides 60-e proceed in high yield to afford, with low asymmetric induction, mixtures of diastereomeric isoxazolines that are readily separated by column chromatography. ' The resolved isoxazolines can be subsequently converted, by hydrogenolysis, to enantiomeric p-amino ketones.CHANTAL LOUIS, SIBEL MILL, VINCENT MANCUSO et CLAUDE HOOTEL~. Can. J. Chem. 72, 1347Chem. 72, (1994. Les rCactions de cycloaddition entre la 3,4,5,6-tktrahydropyridine I-oxyde 1 et les sulfoxydes acCtylCniques homochiraux 6a-e conduisent avec de bons rendements et une induction asymetrique faible a des mtlanges d'isoxazolines diasttrtoisom&res facilement sCparables par chromatographie sur colonne. Les isoxazolines rCsolues peuvent &tre converties, par hydrogtnolyse, en p-aminocCtones Cnantiomkres.[Traduit par la RCdaction] Introduction ene (6) (Scheme 2). Based on the fact that Grignard reactions p -~~i~~ ketones an important ,-lass o~c o m p o u n~s with chiral sulfinate esters proceed stereospecifically with for which the synthesis deserves interest. In this regard, we preinversion of configuration at the sulfur atom (7), the acet~lenic viously reported a new efficient synthesis based on the observasulfoxides 6a-e are assigned the S configuration; the optical tion that 4-isoxazolines 3 can be viewed as masked p-amino purity and the absolute configuration of 6c-e were previously ketones, which could be released by hydrogenolysis of the confirmed by their conversion into the corresponding alkenyl N-0 bond (1) (Scheme 1). Although 4-isoxazolines have derivatives (6).2 proven to be thermally labile heterocycles and display an arrayThe reaction nitrone 1 with the alkynyl sulfoxides 6a-e of rearrangements (2, 31, we established that under carefully gave mixtures of the diastereomeric isoxazolines 7a-e and 8a-e controlled conditions they can be prepared in good yield by (Scheme 3); the large differences in the R,s allowed the comnitrone-alkyne cycloaddition. ~~~~~~~ of the N-0 plete separation of the individual diastereomers of each pair by bond can be performed by hydrogen in the presence of P d C .flash chromatography silica gel. Typical results are PreApplication of this procedure to the synthesis of sented in and deserve some 2-phenacylpiperidine, for example (4, R = C6H,), proceedsAll the cycloadditions proceed with excellent yields. It from nitrone 1 and pheny lacety lene with 70% overall yield. In

Recent developments in chiral non-racemic sulfinyl group chemistry in asymmetric synthesis

“…Hootelé et al had already described the 1,3-dipolar cycloaddition reaction of a 6-membered cyclic nitrone 86 with acetylenic sulfoxides 69 which proceeds readily but with low diastereoselectivities and gives access to enantiomerically pure aminoketones. They subsequently investigated the reactions of the same cyclic nitrone with (Z)-vinylic sulfoxides 87.…”

Total Synthesis of 2‐(2‐Ketoalkyl)‐piperidine Alkaloids (+)‐ Pelletierine, (+)‐Haloxynine and (‐)‐N‐Methyl‐pelletierine via Regioselective Wacker Oxidation

“…The physical and spectroscopic data of the intermediate and final compounds matched very well with the literature data. To the best of our knowledge, there are only three reports available on the synthesis of haloxynine of which two deal with the racemic mixture and one demonstrates diastereoselective [3+2] dipolar cycloaddition …”

“…Therefore, asymmetric synthesis of 2‐substituted piperidine alkaloids has been the target of many laboratories. Various strategies employed for the synthesis include chiral pool, readily available chiral nitrogen compounds, organocatalytic aminoxylation, aza‐Michael reaction, aza‐Henry reaction, aza‐Diels‐Alder, chiral auxiliary approach, transition metal catalyzed reactions, Mannich reaction and chiral bases . From our laboratory, we have reported a few chiral syntheses of pyrrolidine and piperidine alkaloids .…”

Asymmetric [4+2] Cycloadditions Mediated by Sulfoxides

“…Reactions of cyclic nitrone 194 with homochiral alkynyl sulfoxides 8 have also been studied [156]. They were conducted at room temperature (24 h), affording 1:1 mixtures of the diastereoisomeric isoxazolines 196a and 196b in excellent yields (Scheme 93).…”