Synthetic studies on MR304A

Abstract

An attempted synthesis of MR304A 1 [1-(1,2,5-trihydroxy-3-isocyanopent-3-enyl)ethanol] was carried out. Cyclopentenone 3 was set as a key intermediate for the synthesis of 1. By the Honner-Emmons reaction, phosphonate 4 was expected to be synthesized 3, however, the reaction of lithium diethyl methylphosphonate with nitrile 18 and aldehyde 20 was unsuccessful. Samarium diiodide promoted pinacolic coupling reaction of dicarbonyl intermediate was ambitioned as an alternative way. The keto aldehyde 48 was obtained by the sequential treatment of aldehyde 36. The intramolecular carbonyl-coupling reaction of keto aldehyde 48 using samarium diiodide did not proceed cleanly. Cis-(3S, 4R) azetidinone, a key intermediate of Loracarbef, was the target molecule of our synthetic study. For the construction of the cis-substituted azetidinone, the intramolecular cyclization of β-amino acid was attempted. Stereoselective iodoamidation of Z-olefinic allylic alcohol 96 gave the aziridine 114. The regioselective ring opening of 114 with azide furnished α-azido-β-tosylamide ester 117a. Surprisingly, the various deprotection conditions of tosyl group of 117a were fruitless. Alternatively, Sharpless asymmetric aminohydroxylation of α,β-un- saturated ester 144a followed by introduction of azide afforded the α-azido-β-t-butylcarbamate ester 148. The intramolecular cyclization of 140 with Mukaiyama reagent afforded the required cis-substituted azetidinone 141. Introduction of phenoxy acetyl group and oxidation of primary alcohol furnished the desired β-lactam 91. N-Ayalkyl phenylacetamide, KR-25018 167 developed at KRICT, was proved to be a very potent analgesic agent with decreased pungency compared to capsaicin. By structural modification, we tried to improve the therapeutic index, i.e. enhanced analgesic activity, low toxicity and side effects, of phenylacetamides. A systematic replacement of the 3-position of N-aralkylphenylacetamide was performed. Most of the compounds ...