An alternative approach to aminodiols from Baylis-Hillman adducts: stereoselective synthesis of chloramphenicol, fluoramphenicol and thiamphenicol

Abstract

Descrevemos aqui uma nova interpretação para a espectros de banda larga da síntese estereosseletiva de antibióticos de adutos Baylis-Hillman. A estrategia é baseada na preparação de um enocarbamato diretamente do aduto Baylis-Hillman, usando um rearranjo de Curtius. A hidroboração estereosseletiva fornece uma mistura de aminoalcools diasteroisomeros (syn e anti). Após separação cromatográfica, o diasteroisomero syn foi diretamente transformado no antibiótico.We describe herein a new approach for the stereoselective synthesis of broad spectrum antibiotics from Baylis-Hillman adducts. The strategy is based on the preparation of an ene-carbamate directly from a Baylis-Hillman adduct using a Curtius rearrangement reaction. Stereoselective hydroboration furnished a mixture of diastereoisomeric aminoalcohols (syn and anti). After chromatographic separation, the syn diastereoisomer was directly transformed into the antibiotics. Keywords: chloramphenicol, Baylis-Hillman, fluoramphenicol, thiamphenicol, -hydroxymethylketones IntroductionThe indiscriminate use of antibiotics in the Western World for the treatment of innumerous infectious diseases has caused as a principal consequence, the appearance of several microorganism species with drug multiresistance. 1 One of the most obvious strategies to overcome this problem is the utilization of more potent antibiotics but these can cause undesirable effects to patients. In the last few years some older antibiotics have being reintroduced as therapeutics for the treatment of infections caused by drug-multiresistant microorganisms. Among these antibiotics chloramphenicol and its derivatives appear as interesting alternatives.2 Due to toxicological problems, these antibiotics were banned from routine usage and their clinical use was restricted to some specific infectious diseases. Recently several papers 3 and patents 4 reported the utilization of chloramphenicol and its derivatives as valuable options for the treatment of some infectious disease with the toxicity of these drugs being under reinvestigation.Chloramphenicol is the first example of an antibiotic discovered through screening of soil microorganisms 5 and is also the only example of this class of therapeutical compound which was commercialized (Figure 1). 6 There are in the literature numerous papers describing the racemic and asymmetric total syntheses of chloramphenicol and its derivatives, some of them published in the last five years. [7][8][9][10] Natural chloramphenicol and also its derivatives have two asymmetric centers with absolute configuration (R,R) and syn relative stereochemistry. Although showing decreased antibiotic properties, the racemic mixture is also biologically active, with the anti diastereoisomer being completely inactive. 7 Recently our research group reported a strategy to prepare 2-amino-1,3-diols from Baylis-Hillman adducts, 11 which has permitted the synthesis of an oxazolidinone core which exhibited antibiotic properties. An adaptation of this strategy was used recently by us in the s...

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.…”

“…7,8 In this context, our group has previously described the synthesis of chloramphenicol and derivatives as well as the preparation of substituted 2-quinolinones having syn 2-amino-1,3-propanediols in their structures, taking MBH adducts as substrates. 9 The biological and commercial importance of this structural motif calls for the availability of as many as possible alternative methods to prepare these key compounds. Thus, it is described herein a diastereoselective approach to substituted anti 2-amino-1,3-propanediols starting from the MBH reaction.…”

“…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.…”

Applications of Morita-Baylis-Hillman Reaction to the Synthesis of Natural Products and Drug Molecules

“…Such oxazolidines were earlier reported to cleave to afford the chloramphenicol [21]. Subsequently Mateus and Coelho developed an alternate route for the synthesis of amine diols starting from the MBH adducts which allowed them to access chloramphenicol (51), fluoramphenicol (58) and thiamphenicol (59) stereoselectively [22]. Their strategy involved the preparation of ene carbamate from the MBH adduct (54, 55) via a Curtius rearrangement followed by stereoselective hydroboration to obtain the intermediate 2-amino-1,3-diols 56 or 57, respectively (Scheme 7).…”