Reduction of various ketones by red algae

The reduction of acetophenone derivatives, (+)- and (−)-camphorquinones and steroidal ketones using red algae (Cyanidioschyzon merolae 10D and Cyanidium caldarium) was investigated. It was found that fluoro, chloro and bromo acetophenone derivatives 1a–i were reduced with good enantioselectivity. On the contrary, reduction of methyl and methoxy acetophenone 1j–o showed low enantioselectivity. The reduction followed Prelog’s rule, giving the (S)-alcohols in all cases. Moreover, (+)- camphorquinone 5a was reduced to give (−)-3S- exo-hydroxycamphor 5d as the major product with high stereoselectivity in high yield. In addition, it was found that reduction of 5α-androstane-3,17-dione 8a gave the 3α-OH isomer (3α-OH/3β-OH = 76/24) with high stereoselectivity. Overall it was found that C. merolae and C. caldarium were able to reduce various substrates.     

Stereoselective synthesis of substituted exo-glycals from 1-exo-methylene pyranoses

Halo-exo-glycals of the gluco-, manno- and galacto- series, readily prepared by reaction of 1-exo-methylene pyranoses with iodonium dicollidinium triflate (IDCT), undergo Suzuki or B-alkyl Suzuki cross-coupling reactions with boronic acids or alkyl boranes to yield, in a stereoselective manner, functionalized exo-glycals.     

Insights into the stereoselective BF3-catalyzed hetero Diels–Alder reaction of Garner’s aldehyde with Danishefsky’s diene

A trans-2,6-disubstituted tetrahydropyranone was prepared in high yield via a BF₃-mediated hetero Diels–Alder reaction between Danishefsky’s diene and Garner’s aldehyde. Only two of the four possible reaction products were obtained, and excellent diastereoselectivity toward the exo–syn adduct was observed (de = 80%). The origin of this somewhat unusual selectivity can be attributed to the steric interactions between the bulky protecting groups present in the diene and dienophile.     

Lewis acid mediated asymmetric Diels–Alder reactions of chiral 2-phosphonoacrylates

2-Phosphonoacrylates containing four chiral alcohol auxiliaries were efficiently prepared and evaluated in Lewis acid mediated Diels–Alder reactions. Under the activation of SnCl₄, all reactions performed in CH₂Cl₂ at ?65 °C exclusively afforded the endo (endo-to-carboxylate) cycloadducts with dr’s ranging from 50:50 to >99:1. The best facial selectivity was obtained from the substrate bearing a (?)-phenylmenthyl group, to give adducts as (dr >99:1) or almost as (dr = 99:1) single diastereomers. Detailed strategies for the structural elucidation of the cycloadducts as well as a rationalization of the observed stereoselectivity are described.     

Wittig reaction of glycosyl phosphonium salts: a stereoselective route to C-disaccharides and C,O-trisaccharides

C-Disaccharides and C,O-trisaccharides, with a quaternary anomeric center, were prepared in good yields and excellent stereoselectivity by a route involving the Wittig reaction of glycosyl phosphonium salts and hydrogenation or glycosidation of exo-glycals as key steps.     

Catalytic asymmetric carbon–carbon bond forming reactions catalyzed by tetrahydroisoquinoline (TIQ) N,N′-dioxide ligands

The use of TIQ-N,N′-dioxide ligands in asymmetric C–C bond forming reactions is described. In the Michael addition of cyclohexane-1,3-dione and malonates to β,γ-unsaturated α-ketoesters, excellent yields (up to 93%) and moderate to good enantioselectivities (70–89% ee) were obtained. The catalytic hetero-ene reaction of 2-methoxypropene with phenylglyoxal gave the ene product in excellent yield (95%) with moderate enantioselectivity (77% ee). The catalyst system performed well at temperatures ranging from 0 to 30 °C and relatively low catalyst loading (0.2–5 mol %) with dichloromethane being the preferred solvent for all reactions.     

Photoinitiated Thiol-ene Reactions of Enoses: A Powerful Tool for Stereoselective Synthesis of Glycomimetics with Challenging Glycosidic Linkages

Thioglycosides and C-glycosides represent pharmacologically useful classes of glycomimetics that possess a high degree of biological stability. One emerging tool for the stereoselective synthesis of thioglycosides is the photoinitiated addition of thiols to unsaturated sugars. Moreover, thiyl radical-mediated reactions of exo-glycals and 1-substituted endo-glycals offer facile routes to β-C-glycosidic structures. This Concept article summarizes the thiol-ene coupling strategies developed recently by our group and Somsák's group for the synthesis of several kinds of glycomimetics which are difficult to synthesize by conventional methods. One unusual characteristic of the thiol-ene reactions of endo-glycals is that heating inhibits, whereas cooling promotes the reaction. This unique temperature dependence as well as the effects of the enose structures and thiol configurations on the efficacy and stereoselectivity of the reactions are also discussed.     

Stereoselectivity of the captodative alkenes 1-acetylvinyl arenecarboxylates in Diels-Alder reactions with cyclic dienes and stereospecific rearrangement of their bicyclo[2.2.n] α-ketol adducts

Captodative alkene 1-acetylvinyl p-nitrobenzenecarboxylate 1a was evaluated for its reactivity and stereoselectivity with cyclohexadiene (10) in Diels-Alder reactions, showing exclusive endo preference. The two hydrolyzed products of the endo and the exo adducts obtained from the Diels-Alder cycloaddition between 1a and cyclopentadiene (7) were 8b and 9b. When treated with mCPBA, a ring expansion took place to stereospecifically yield the novel 3-oxatricyclo[3.3.1.0^2,4]nonanone acyloins 15 and 16, respectively. In the case of the α-ketol bicyclo[2.2.2]octanes 11b and 12b, the epoxidation/Baeyer-Villiger cascade process was preferred, resulting in the syn ketoepoxide 19b from each isomer. A synthetic application of this kind of transformation was carried out by reacting ketols 8b and 9b with an excess of mCPBA through a five-step cascade process to yield the bicyclic lactone 27 as a potential precursor of racemic β-carbaxylose.     

Chiral quaternary alkylammonium ionic liquid [Pro-dabco][BF4]: as a recyclable and highly efficient organocatalyst for asymmetric Michael addition reactions

A novel series of chiral quaternary ammonium ionic liquids have been synthesized and shown to be very effective catalysts for the asymmetric Michael addition reactions of ketones and aldehydes to nitroolefins with excellent yields (up to 100%), diastereoselectivities (syn/anti = 99:1), and enantioselectivities (up to 97%). The catalytic system, an ionic liquid organocatalyst in [Bmim][BF₄], could be reused five times without a significant loss in catalytic activity or stereoselectivity.     

Simple amphiphilic isosteviol–proline conjugates as chiral catalysts for the direct asymmetric aldol reaction in the presence of water

Two novel amphiphilic catalysts 3 and 4 were synthesized by the condensation of isosteviol with l-proline in a one-pot process. With only 1 mol % loading, the catalyst 3 showed excellent activity (up to >99% yield) and stereoselectivity (up to 99:1 dr, >99% ee) for the direct aldol reaction of cyclohexanone and substituted benzaldehydes at room temperature in the presence of water. In addition, solvent effects, catalyst loading, substrate scope, temperature, and the influence of water on the reactions were investigated. These results demonstrate that the catalysts with a chiral concave and hydrophobic substituent in the 4-position of l-proline furnished high activity and stereoselectivity for the reaction.     

Linear polystyrene anchored l-proline,new recyclable organocatalysts for the aldol reaction in the presence of water

Two l-proline-based linear polystyrene anchored catalysts 1a and 1b have been synthesized efficiently. The catalytic activities and stereoselectivity of these readily tunable and amphiphilic organocatalysts were evaluated in the direct asymmetric aldol reaction of various aromatic aldehydes and ketones. By using 5 mol % of the catalysts, the corresponding products of the aldol reaction were obtained in good yields (up to 94%) and with excellent anti diastereoselectivities (up to 96:4) and enantioselectivities (up to 96% ee) in DMF in the presence of water. The yields of these reactions in a ketone/water mixture were lower than those in wet DMF (up to 76%). However, the stereoselectivity was comparable (up to 93:7 anti/syn ratio and 95% ee, respectively). In addition, catalysts 1a and 1b could be recovered by a simple precipitation and filtration process. They could also be re-used for at least five times without obvious loss of catalytic efficiency.     

Synthesis of chiral C/N-functionalized morpholine alcohols: study of their catalytic ability as ligand in asymmetric diethylzinc addition to aldehyde

A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxymethyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties. The asymmetric addition of diethylzinc to benzaldehyde in the presence of 10 mol % of chiral C/N-functionalized morpholine alcohols gave 1-phenyl-1-propanol in 59–81% yield with 10–30% ee. The addition of 10 mol % of n-butyl lithium to the reaction mixture resulted in a significant enhancement of the stereoselectivity in the case of ligands bearing the two geminal phenyl substituents on the backbone. In the presence of n-butyl lithium and using (S)-3-(hydroxydiphenylmethyl)morpholine (S)-19 as the chiral promoter, (S)-1-phenyl-1-propanol was obtained in 81% yield with 76% ee. The geminal diphenyl-class of morpholine ligands was examined for the diethylzinc addition to four different aldehydes in the presence of n-butyl lithium. (S)-N-Benzyl-3-(hydroxydiphenylmethyl)morpholine (S)-27 was found to be most enantioselective in the case of 4-methoxybenzaldehyde to give (R)-alcohol in 87% yield with 80% ee. Catalysts (S)-19 and its N-methyl derivative (S)-26 gave alcohols with an (S)-absolute configuration while the N-benzylated derivative (S)-27 gave the opposite enantiomeric products. The tentative transition state models to account for the observed product stereoselectivity with morpholine ligands holding the geminal diphenyl group on the β-amino alcohol segment are proposed.     

Heck-type cross-coupling between halo-exo-glycals and endo-glycals: a practical way to achieve C-glycosidic disaccharides

An effective Heck-type cross-coupling reaction between halo-exo-glycals and endo-glycals to achieve C-glycosidic disaccharides has been developed. Using Pd(OAc)₂ as the catalyst, dppp as ligand and K₂CO₃ as base, the reactions gave C-glycosidic products in good to excellent yields with exclusive stereochemistry.     

Insertion of the p-complex structure of silylenoid H2SiLiF into X–H bonds (X = C,Si, N,P, O,S, and F)

The insertion reactions of the p-complex structure (A) of silylenoid H₂SiLiF into XH_n molecules (X = C, Si, N, P, O, S, and F; n = 1–4) have been studied by ab initio calculations at the G3(MP2) level. The results indicate that the insertion reactions of A into X–H bonds proceed via three reaction paths, I, II, and III, forming the same products, substituted silanes H₃SiXH_n − 1 with dissociation of LiF, respectively, and all insertion reactions are exothermic. All the seven X–H bonds can undergo insertion reactions with A via path I and II, but only four of them, C–H, Si–H, P–H, and S–H, undergo insertion reactions via path III. The following conclusions emerge from this work: (i) the X–H insertion reactions of A occur in a concerted manner via a three-membered ring transition state; (ii) for path I and II, the stabilization energies of the A–XH_n complexes decrease in the order HF > H₂O > H₂S > NH₃ > SiH₄ > CH₄; (iii) for path I and II, the greater the atomic number of heteroatom (X) in a given row, the easier the insertion reaction of XH_n hydrides and the larger the exothermicity, and for the second-row hydrides, the reaction barriers are lower than for the first-row hydrides; (iv) The barriers of path I are lowest in those of three pathways with the exception of A + SiH₄ system, which barrier of path III is lowest. Moreover, the present study demonstrates that both electronic and steric effects play major roles in the course of insertion reactions of A into X–H bonds.     

C–H bond addition and copolymerization reactions of N-arylmaleimides: Fundamentals of coagent-assisted polymer cross-linking

Solid-state rheometry and model compound reactions are used to investigate free radical reactions of N-arylmaleimide coagents with saturated and unsaturated polymers. N,N′-m-phenylene dimaleimide (BMI) is shown to provide superior cross-link densities over diacrylate and diallyl coagents for all of the polymers studied, including linear low density polyethylene (LLDPE), poly(ethylene oxide) (PEO), cis-poly(butadiene) (PBD) and cis-poly(isoprene) (PIP). Studies of the N-phenylmaleimide (NPM) + cis-cyclooctane system show that C–H bond addition to yield N-aryl-2-alkylsuccimide grafts is the predominant reaction pathway, as opposed to maleimide homopolymerization. In contrast, peroxide-initiated reactions of cis-cyclooctene with small NPM concentrations generate highly alternating poly(cycloctene-alt-N-phenylmaleimide) in high yield, indicating that unsaturated mers in materials such as PBD engage maleimides in an efficient alternating copolymerization between electron-rich and electron-deficient monomer pairs. Factors that affect the reactivity of different polymers in these C–H bond additions and alternating copolymerizations are discussed.     

Efficient access to disubstituted exo-glycals. Application to the preparation of C-glycosyl compounds

Efficient methods of preparation of disubstituted exo-glycals by palladium cross-coupling reaction on the readily available dibromo exo-glycal and methoxycarbonyl exo-glycal have been developed. Hydrogenation of these new monosubstituted and disubstituted exo-glycals proceeded with a high stereocontrol and led to original C-glycosyl compounds.     

Cryoradiolytic reduction of heme proteins: Maximizing dose-dependent yield

Radiolytic reduction in frozen solutions and crystals is a useful method for generation of trapped intermediates in protein-based radical reactions. In this communication we define the conditions which provide the maximum yield of one electron-reduced myoglobin at 77 K using ⁶⁰Co γ-irradiation in aqueous glycerol glass. The yield reached 50% after 20 kGy, was almost complete at ∼160 kGy total dose, and does not depend on the protein concentration in the range 0.01–5 mM.     

Advanced procedure for the enzymatic ring opening of unsaturated alicyclic β-lactams

Enantiopure β-amino acids 1a–4a and β-lactams 1b–4b were prepared simultaneously through the lipolase-catalysed enantioselective ring opening of unsaturated racemic β-lactams (±)-1-(±)-4. High enantioselectivities (E>200) were observed when the reactions were performed with 1 equiv of water in iPr₂O at 70 °C. The resolved (1R,2S)-amino acids (yield⩾45%) and (1S,5R)-, (1S,6R)- and (1S,8R)-lactams (yield⩾47%) could be easily separated. The ring opening of lactam enantiomers 1b–4b with 18% HCl afforded the corresponding β-amino acid hydrochlorides 1c·HCl–4c·HCl (ee >95%).     

4-trans-Amino-proline based di- and tetrapeptides as organic catalysts for asymmetric C–C bond formation reactions

4-trans-Amino-proline based di- and tetrapeptides have been successfully applied as chiral organocatalysts in the enantioselective conjugate addition of nitroalkanes to cyclic enones and the direct aldol reaction. Two 4-trans-amino-proline residues were shown to be sufficient enough to catalyze the conjugate addition reactions with up to 88% ee and up to 100% yield. It has been demonstrated that 4-trans-amino-proline based di- and tetrapeptides are significantly more active than l-proline (at 30 mol %) and can catalyze the direct aldol reaction with good yield and enantioselectivity within 3 h and at lower catalyst loading (5 mol %).