Hyphenating the curtius rearrangement with Morita-Baylis-Hillman adducts: synthesis of biologically active acyloins and vicinal aminoalcohols

Abstract

Um rearranjo de Curtius, utilizando adutos de Morita-Baylis-Hillman como substrato, foi realizado em uma sequência que permitiu a síntese de várias hidroxi-cetonas (aciloínas) com uma grande diversidade estrutural e com bons rendimentos globais. Por sua vez, essas aciloínas foram transformadas em 1,2-amino-alcoóis de configuração relativa anti, através de uma etapa de aminação redutiva altamente diastereosseletiva. A utilidade sintética dessas abordagens foi demonstrada através das sínteses totais da (±)-bupropiona, fármaco utilizado no tratamento na síndrome de abstinência de fumantes e da (±)-espisulosina, um potente agente anti-tumoral isolado inicialmente de uma fonte marinha.Using Morita-Baylis-Hillman adducts as substrates, the Curtius rearrangement was performed in a sequence that allowed the synthesis of several hydroxy-ketones (acyloins) with great structural diversity and in good overall yields. These acyloins in turn were easily transformed into 1,2-anti aminoalcohols through a highly diastereoselective reductive amination step. The synthetic utility of these approaches was exemplified by performing the syntheses of (±)-bupropion, a drug used to treat the abstinence syndrome of smoker and (±)-spisulosine, a potent anti-tumoral compound originally isolated from a marine source. Keywords:Curtius rearrangement, Morita-Baylis-Hillman, drugs, aminoalcohols, acyloins IntroductionThe formation of new C-N bonds by incorporation of a nitrogen atom into a molecule is a fundamental transformation in organic chemistry, since it allows accessing many valuable compounds. 1 Basically, this can be achieved by nucleophilic substitution reactions or by electrophilic amination reactions. 2 A C-N bond can also be built through rearrangement reactions. For instance, Lossen, 3 Beckman, 4 Schmidt 5 and Curtius 6 rearrangements are processes which allow the efficient formation of a new C-N bond from carbonyl containing derivative compounds.The Curtius rearrangement is a thermal decomposition of a carbonyl azide leading to an isocyanate. This stereospecific rearrangement provides carbamates or amines in good overall yields and selectivities. Unfortunately, this rearrangement has the drawback that low molar mass acyl azides present an explosion hazard. 7 This safety issue has limited the industrial use of this transformation until recently, when Am Ende et al. 8 reported a new experimental protocol, which enabled the use of this reaction under safer conditions even when conducted on a large scale. This and other protocols have revived interest in this rearrangement, particularly for industrial purposes. 9 Regarding the potential of this rearrangement, our group has recently reported the preparation of some carbamates from Morita-Baylis-Hillman (MBH) adducts. 10 Curtius rearrangement would be the best way to achieve our target, since the carboxyl group in this structure is needed to perform this rearrangement. Thus, when an acid derived from a MBH adduct was treated with sodium azide, heated at reflux and treated subsequently w...

Diastereoselective synthesis of substituted 2-amino-1,3-propanediols from Morita-Baylis-Hillman adducts

“…General procedure for the preparation of oxo-derivatives (9)(10)(11) Into a stirred solution of the acetylated compounds 21-23 (1 mmol) in 10 mL of methanol (at -72 °C), it was passed a slow flow of ozone. The reaction was followed by TLC until no starting material was detected.…”

“…They can be also used against rheumatism, cancers, diabetes retinopathy, respiratory system diseases and twitch after subarachnoidal hemorrhage. 10 Our approach is based on a diastereoselective reductive amination of the 2-oxo-1,3-propanediol derivatives (9)(10)(11), that are easily prepared from double bond ozonolysis of an allylic diol. The latter is promptly prepared by chemoselective ester reduction of Morita-Baylis-Hillman adducts (12)(13)(14) after silylation of the secondary hydroxyl group.…”

“…The relative stereochemistry of our aminodiols is expected to be controlled during the reductive amination step of the oxo-diols (9)(10)(11). Most probably, this control could be exerted by the presence of a ligand with chelating properties in α position, based on the Cram-chelate model of 1,2-induction.…”

The synthesis of bupropion hydrochloride under greener and safer conditions utilizing flow technologies

“…Alternatively, the use of an activated alcohol at the alpha position would circumvent the issues of using bromine as previously demonstrated by Coelho and co-workers. 33 Unfortunately, in the context of this work the approach was deemed unattractive as it required two additional steps (5 vs.…”