Marielle Lemaire

Asymmetric Self- and Cross-Aldol Reactions of Glycolaldehyde Catalyzed by D-Fructose-6-phosphate Aldolase†

Aldol additions are key chemical reactions for the construction of chiral complex polyhydroxylated molecules. Recent developments in direct aldol additions using bio-, organo-, and metal catalysts are promising since these methodologies do not require separate generation of enolate equivalents and thus improve the atom economy of the transformation. 2,5–8] Aldehydes have been regarded as highly interesting donors in aldol reactions, because the products formed are themselves aldehydes that can be used in further aldol additions for the construction of complex polyfunctional molecular frameworks. Hence, the direct catalytic cross-aldol reaction of aldehydes constitutes a challenge for these methodologies. 10] Selfand cross-aldol reactions were achieved by organocatalysis in N,N-dimethylformamide (DMF) using simple aliphatic and aromatic aldehydes. Selfand cross-aldol additions involving glycolaldehyde derivatives are of paramount interest because they allow access to polyol architectures. 13] Organocatalytic selfand cross-aldol additions of free glycolaldehyde failed to provide promising results. 16] A successful self-aldol addition was accomplished in DMF, but it was limited to glycolaldehyde derivatives with electron-rich a-alkyloxy or bulky asilyloxy protecting groups. No further additions were observed on the corresponding aldol adducts, a feature essential for a two-step aldol-based synthesis of carbohydrates. This approach was used to prepare protected hexoses: a direct organocatalytic self-aldol addition was followed by a direct metal-catalyzed aldol addition. In cross-aldol additions, the organocatalyst cannot selectively control the donor and acceptor roles; this is governed by the aldehyde structure and reactivity. Therefore, in the presence of simple aliphatic aldehyde donors 13] O-protected glycolaldehyde derivatives act invariably as acceptors, likely because they are kinetically disfavored as donors. Biocatalytic synthetic strategies for carbohydrates and their analogues require water-soluble polyhydroxyaldehyde derivatives as acceptor substrates for aldolases. 20] Multistep strategies have suffered from the laborious and costly isolation of sensitive deprotected hydroxyaldehydes which are usually obtained by chemical means. In addition, the vast majority of reported biocatalytically prepared carbohydrates and related products are ketoses. This is because aldolases specific for aldose-type sugars are scarce in nature; 2-deoxyribose-5-phosphate aldolase (DERA) is a notable exception and actually functions as a deoxysugar aldolase. Hence, cross-aldol reactions of aldehydes have been a limited field for biocatalysis, and DERA is the only enzyme known to catalyze the stereoselective cross-aldol addition of acetaldehyde to other aldehydes. However, the low conversion rates of this enzyme with non-phosphorylated, unnatural substrates and its inability to generate two consecutive hydroxylated positions with each newly formed bond limit considerably its scope of applicability. Consequently, the biocatalytic selfand cross-aldol additions of glycolaldehyde are a challenge for the cascade two-step synthesis of carbohydrates. Recently, we reported the synthesis of iminosugars and other polyhydroxylated compounds catalyzed by d-fructose6-phosphate aldolase (FSA). This aldolase shows an unprecedented tolerance for donor substrates such as dihydroxyacetone (DHA), hydroxyacetone (HA), and 1-hydroxy2-butanone. In the course of our investigations on the catalytic properties of FSA, we discovered a new and unexpected activity of paramount importance: its ability to catalyze the direct stereoselective self-aldol addition of glycolaldehyde (GA) (1) to furnish d-( )-threose (2) (Scheme 1). In this reaction, GA (1) acts as both the

Chemo-enzymatic synthesis of precursors of fagomine and 1,4-dideoxy-1,4-imino-D-arabinitol

Abstract The enantioselectivity of transketolase towards, α-hydroxy-aldehydes is used to prepare compounds bearing two asymmetric centres, precursors of natural products: 2,3-dideoxynojirimycine (fagomine), 1,4-dideoxy-1,4-imino-D-arabinitol, and its oxidised form.

Fructose-1,6-bisphosphate aldolase and transketolase : Complementary tools for the de novo syntheses of monosaccharides and analogues

Abstract This paper reports a new synthesis of bromoacetol phosphate and dihydroxyacetone phosphate for use in fructose-1,6-bisphosphate aldolase (FB-aldolase) catalyzed syntheses. Then the activities of FB-aldolase and transketolase towards polyhydroxybutanal analogues of erythrose and erythrose-4-phosphate were studied. These activities were high enough to allow the syntheses of rare heptulose-1-phosphates of the d and l series.

2- And 8-functionalized 1,4,7,10-tetraoxaspiro[5.5]undecanes. II: Synthesis of (+)-E,E and (±)-Z,E structures from chiral isopropylideneglycerols

Abstract Using a short synthetic protocol, the enantiomerically pure ( + )-E,E title compound was made from (S,S)-diisopropylidenetriglycerol 4 in order to obtain a reference for correlations in this unexplored series. Analogously (S,R)-diisopropylidenetriglycerol 11 would afford the (±)-Z,E isomer which was also prepared. Conformations were deduced from 1 H NMR data.

Synthesis of specially designed probes to broaden transketolase scope

Efficient, biocompatible, stereospecific strategies were developed to prepare eight probes to assay transketolase (TK) variants with new substrate specificities. The structure of these probes combines a sugar moiety (D‐threo or L‐erythro ketose, or D‐threo aldose) with the side chain of an amino acid (Ala, Leu, Val, Met, Thr) for inu2005vivo detection of new TK activities using amino acid auxotrophs. To obtain D‐threo ketose probes, biocatalysts, such as transketolase and fructose‐6‐phosphate aldolase Ala129Ser, were used whereas L‐erythro ketoses and D‐threo aldose probes were synthesized by the way of organocatalysis or Sharpless dihydroxylation as sustainable alternative key steps to biocatalysis.

Chemo-enzymatic synthesis of new protected aldoketoses: Intermediates in the biosynthesis and chemical synthesis of nojirimycin and mannojirimycin

Abstract Condensation of dihydroxy acetone phosphate (DHAP) on new hydroxy-aldehydes catalysed by fructose-1,6-diphosphate aldolases provides two aldoketoses presumed intermediates in the biosynthesis of nojirimycin and mannojirimycin, as well as useful precursors for the chemical synthesis of these aminosugars and some analogues.

Enzymatic resolution of a 1,2-cyclic sulphite glycerol derivative

Abstract cis -2-Oxo-5-hydroxymethyl-1,3,2-dioxathiolane 2a can be efficiently resolved by a lipase from Pseudomonas cepacia- catalysed acylation reaction with vinylbutyrate. Compound 2a was directly prepared from glycerol in one step. This first lipase-catalysed resolution of a cyclic sulphite derivative provides a potentially useful activated chiral synthon.

2- and 8- functionalized 1,4,7,10-tetraoxaspiro[5.5]undecanes. I. Synthesis of (±)-E,E and (±)-Z,E structures.

Abstract The synthesis of (±)-E,E and (±)-Z,E 2,8-dihydroxymethyl-1,4,7,10-tetraoxaspiro[5.5]undecane is described. The selective modification of one sidechain is examined for the (±)-E,E isomer, and a tetraoxygenated analogue of a commonly encountered insect pheromone is prepared.

Expanding the reaction space of aldolases using hydroxypyruvate as a nucleophilic substrate

B is a clean, renewable and abundant resource that can be converted to bio-char, bio-oil and fuel gas through various thermochemical processes. Conversion of biomass for high value products is an important development direction for biomass utilization, which has attracted more attention. In this study, a new method of biomass pyrolysis with exogenous nitrogen introduced was proposed. The influence of NH3 on the property of bamboo pyrolysis process and products characteristics was investigated with variant approaches (e.g. elemental analysis, automatic adsorption equipment, X-ray photoelectron spectroscopy and CHI760 electrochemical workstation) and as well as the influence of KOH (as activator). The results showed that, the specific surface area, the content of nitrogen and nitrogen-containing functional groups of bio-char increased significantly with NH3 introduced in. On the other hand, with the addition of KOH, the yield of bio-char increased obviously and it increased gradually with increasing KOH amount, and the specific surface area increased dramatically to 1873.17 m2 g-1. The content of nitrogen in bio-char increased greatly with KOH introduced in, especially the content of pyridinic-N and pyrrolic/pyridone-N, while it decreased slightly with increasing KOH amount, but nitrogen content was still relative high (9.1-10.4 wt.%). The formation mechanism of nitrogen-containing functional groups was proposed. Besides, electrochemical analysis showed that the specific capacitance of bio-char electrodes increased with increasing KOH content, and the largest specific capacitance could reach to 187 F g-1 at 1 A g-1 with good cycling stability. Therefore, it could be concluded that biomass nitrogen-enriched pyrolysis was a promising method for more efficient utilization of biomass resources.A insoluble palladium catalyst (Pd-pol) was obtained by copolymerization of the metal containing monomer Pd(AAEMA)2 [AAEMA− = deprotonated form of 2-(acetoacetoxy)ethyl methacrylate] with ethyl methacrylate (co-monomer) and ethylene glycol dimethacrylate (cross-linker), followed by in situ reduction of Pd(II) to Pd(0), to give polymer stabilized metal nanoparticles. The good swellability in water exhibited by Pd-pol rendered it an ideal potential catalyst for reactions carried out in a green solvent, such as water, since the migration of the reagents to the active sites would not be hampered by the solid support. With the aim to develop innovative catalytic processes that enable chemical transformations to be performed under mild and sustainable conditions with high efficiency, we decided to evaluate the catalytic activity of Pd-pol for several important organic reactions using water as solvent. Pd-pol resulted highly active and selective in catalyzing (figure 1): the Suzuki-Miyaura coupling between aryl bromides or activated aryl chlorides and phenylboronic acid; the oxidation of benzyl alcohols to aldehydes; the reduction of quinolines and nitroarenes by H2 or NaBH4. Pd-pol was recyclable for several consecutive runs (for example, at least 12 times in the nitroarene reduction). TEM analyses carried out on the catalyst showed that the active species were supported palladium nanoparticles having a mean size of 4 nm, which did not aggregate with the recycles. Recently, due to their low cost, Ni catalysts have been employed in several organic reactions (mainly hydrogenations). In this context, we synthetized a Ni catalyst similar to Pd-pol, starting from Ni(AAEMA)2 and we employed it as active and recyclable, insoluble catalyst for the reduction of different nitroarenes to give the corresponding anilines, under sustainable conditions. All these results proved that the proposed Pd or Ni based composite materials are excellent hybrid structures as efficient and reusable catalysts.A amino acids are versatile structures readily available by a number of methods and are accessible using very few transformations from economical starting materials. They can be functionalized by many chemical functions and offer a wide range of possible transformations. Particularly, unsaturated α-amino acids give access to many synthetic applications in all fields of chemistry. Among them, metal catalyzed cross-coupling reactions and cross metathesis are commonly used to generate peptide modifications and cyclization. They are very interesting and useful tools for “Click” Chemistry in peptidomimetic drug design or covalent modification of proteins. They can also be incorporated in compounds as beta-turn inducer to promote secondary structures. Finally they can be used for the preparation of stapled peptides. Some such amino acids are commercially attainable in enantiomerically pure form. Here, we present a stereoselective approach to synthesize unsaturated α-amino acids in optically active form. As a starting amino acid synthon for the asymmetric synthesis of amino acids NiII square-planar complexes of Schiff ’s bases of propargylglycine with chiral auxiliary (S)-2-N-(N`-benzyl-prolyl)aminobenzophenone (BPB) (1) was taken. As a result effective methods of asymmetric synthesis for novel enantiomerically enriched derivatives of (S)-propargylglycine (S)-propargylglycine (ee > 80%) was developed.

2- and 8- functionalized 1,4,7,10-tetraoxaspiro[5.5]undecanes.: III. Resolution of a (±)-E,E structure by enzymatic and chemical methods.

Abstract The optical resolution of a (±)-E,E-2,8-disubstituted-1,4,7,10-tetraoxaspiro[5.5] undecane system was carried out by lipase-catalyzed hydrolysis of a symmetrical diester and also by monosubstitution with a chiral amine. Configurations of the new products were assigned by chemical correlations.