Palladium-Catalyzed Divergent Cyclopropanation by Regioselective Solvent-Driven C(sp3 )-H Bond Activation.

Reported is a tandem palladium-catalyzed Heck/regioselective C(sp3 )-H activation reaction for the divergent synthesis of spiro- and fused-cyclopropanated indolines from N-methallylated 2-bromoarylamides. The regioselectivity of the C-H bond activation in the σ-alkylPdII intermediate is controlled by the solvent used. DFT calculations suggest that the polarity of solvent molecules could influence the transition-state energy, leading to a bifurcation of the C-H bond activation in the σ-alkylPdII intermediate.

Stereoselective Pd-catalyzed etherification and asymmetric synthesis of furanomycin and its analogues from a chiral aziridine.

A chiral aziridine was utilized for the synthesis of the anti-bacterial natural amino acid L-(+)-furanomycin, and its analogues including 5'-epi-furanomycin and norfuranomycin. Key steps of this synthesis are the stereoselective Pd-catalyzed etherification for diallyl ethers and ring closing metathesis.

CAL-B catalyzed desymmetrization of 3-alkylglutarate: "olefin effect" and asymmetric synthesis of pregabalin.

CAL-B catalyzed desymmetrization of prochiral 3-alkylglutaric acid diesters was performed to prepare optically active 3-alkylglutaric acid monoesters bearing various alkyl substituents, including methyl, ethyl, propyl and allyl groups. Allyl esters showed far better stereoselectivity among the alkyl esters, suggesting possible π-π interactions between the olefin of the substrate and the Trp104 or His224 side chains at the enzyme active site. Based on this reaction, the synthesis of (S)-(+)-3-aminomethyl-5-methylhexanoic acid (pregabalin) was achieved with a 70% overall yield.

Highly stereoselective directed reactions and an efficient synthesis of azafuranoses from a chiral aziridine.

Polyhydroxylated pyrrolidines, such as biologically important azafuranoses represented by the natural product (+)-2,5-imino-2,5,6-trideoxy-gulo-heptitol and its C(3)-epimer, were elaborated from a commercially available enantiomerically pure (2R)-hydroxymethylaziridine by highly stereoselective directed reactions in more than 61% overall yield. At first, the nucleophile 2-trimethylsilyloxyfuran was directed to (2R)-aziridine-2-carboxaldehyde by ZnBr2 to yield the unusual anti-addition product as a single isomer via the chelation-controlled transition. The ring opening of aziridine was followed by conjugate addition to give a cis-fused bicycle, which was converted to the target molecule after the required reductive operations.

The sphingosine-1-phosphate derivative NHOBTD inhibits angiogenesis both in vitro and in vivo.

Sphingosine-1-phosphate (S1P) plays an important role in angiogenesis by stimulating DNA synthesis, chemotactic motility, and early blood vessel formation. Accordingly, the S1P signaling pathway is an attractive target for novel anti-angiogenic therapeutics. Here, we describe a small synthetic derivative of S1P that acts as an anti-angiogenic agent. We found that the S1P derivative NHOBTD [N-((2S,3R)-3-hydroxy-1-morpholino-4-(3-octylphenyl)butan-2-yl)tetradecanamide] suppressed S1P-induced invasion and tube formation by human umbilical vein endothelial cells. NHOBTD also suppressed S1P signaling, as seen by destabilization of hypoxia inducible factor-1 alpha (HIF-1α) and secretion of VEGF, a transcriptional target of HIF-1α. Moreover, NHOBTD profoundly blocked endogenous neovascularization of the chick embryo chorioallantoic membrane, without rupturing any existing vessels. Together, these results demonstrate that NHOBTD is a new anti-angiogenic molecule that is capable of perturbing S1P signaling, and provides the basis for developing new anti-angiogenic drugs.

Asymmetric synthesis of 1-deoxyazasugars from chiral aziridines.

A general and facile synthesis of enantiopure 1-deoxyazasugars was achieved from stereoselective dihydroxylation of a common synthetic intermediate, piperidine ring fused oxazolidin-2-one, originating from a commercially available starting substrate, chiral aziridine-2-carboxylate, in high yields.

3,4-Disubstituted oxazolidin-2-ones as constrained ceramide analogs with anticancer activities.

Heterocyclic analogs of ceramide as 3-alkanoyl or benzoyl-4-(1-hydroxy-2-enyl)-oxazolidin-2-ones were designed by binding of primary alcohol and amide in sphinogosine backbone as a carbamate. They were synthesized by addition of acyl halide to the common ring 4-(1-t-butyldimethylsilyloxyhexadec-2-enyl)-oxazolidin-2-one which was elaborated from chiral aziridine-2-carboxylate including stereoselective reduction and ring opening reactions as key steps. Other analogs with different carbon frame at C4 position which is corresponding to the sphingoid backbone were prepared from 3-cyclopentanecarbonyl-4-(1-t-butyldimethylsilyloxybut-2-enyl)-oxazolidin-2-one and straight and cyclic alkenes by cross metathesis. All compounds were tested as antileukemic drugs against human leukemia HL-60 cells. Many of them including propionyl, cyclopentanoyl and p-nitrobenzoyl-4-(1-hydroxyhexadec-2-enyl)-oxazolidin-2-ones showed better antileukemic activities than natural C2-ceramide with good correlation between cell death and DNA fragmentation. There is a drastic change of the activities by the carbon chain lengths at C4 position. Cytotoxicity was induced by caspase activation without significant accumulation of endogenous ceramide concentration or any perturbation of ceramide metabolism.

Dynamic thermodynamic resolution: advantage by separation of equilibration and resolution.

In the investigation of a chemical reaction, researchers typically survey variables such as time, temperature, and stoichiometry to optimize yields. This Account demonstrates how control of these variables, often in nontraditional ways, can provide significant improvements in enantiomeric ratios for asymmetric reactions. Dynamic thermodynamic resolution (DTR) offers a convenient method for the resolution of enantiomeric products in the course of a reaction. This process depends on an essential requirement: the equilibration of the penultimate diastereomers must be subject to external control. As a general case, the reaction of A(R), A(S) with B under the influence of the chiral species, L*, gives resolved products C(R) and C(S). In the first step of dynamic resolution under thermodynamic control, the enantiomeric reactants A(R) and A(S) and L* form the diastereomers A(R)/L* and A(S)/L*. The equilibrium between A(R) and A(S) can be rapid, slow, or not operative, and L* can represent a ligand, an auxiliary, or a crystallization process that provides a chiral environment. Second, the populations of the diastereomers are controlled, usually by thermal equilibration. Finally, the reaction of the diastereomers with a reagent B provides the enantiomeric products C(R) and C(S). The control of the diastereomeric equilibrium distinguishes DTR from other resolution techniques. By contrast, physical resolutions separate thermodynamically stable, nonequilibrating diastereomers, and dynamic kinetic resolutions utilize kinetic control for reactions of rapidly equilibrating diastereomers. The dynamic thermodynamic resolutions discussed in this Account illustrate cases of significantly improved enantioselectivities using this technique. Although many of the well-recognized cases come from organolithium chemistry, the principles are general, and we also present cases facilitated by other chemistries. This approach has been used to control enantioselectivities in a number of different reactions, with improvements in enantiomeric ratios up to 99% from essentially racemic reactants.

Molecular basis for the stereoselective ammoniolysis of N-alkyl aziridine-2-carboxylates catalyzed by Candida antarctica lipase B.

Candida antarctica lipase B catalyzed the stereoselective ammoniolysis of N-alkyl aziridine-2-carboxylates in tBuOH saturated with ammonia and yielded the (2S)-aziridine-2-carboxamide and unreacted (2R)-aziridine-2-carboxylate. Varying the N-1 substituent on the aziridine ring changed the rate and stereoselectivity of the reaction. Substrates with a benzyl substituent or a (1'R)-1-phenylethyl substituent reacted approximately ten times faster than substrates with a (1'S)-1-phenylethyl substituent. Substrates with a benzyl substituent showed little stereoselectivity (E=5-7) while substrates with either a (1'R)- or (1'S)-1-phenylethyl substituent showed high stereoselectivity (D>50). Molecular modeling by using the current paradigm for enantioselectivity-binding of the slow enantiomer by an exchange-of-substituents orientation-could not account for the experimental results. However, modeling an umbrella-like-inversion orientation for the slow enantiomer could account for the experimental results. Steric hindrance between the methyl in the (1'S)-1-phenylethyl substituent and Thr138 and Ile189 in the acyl-binding site likely accounts for the slow reaction. Enantioselectivity likely stems from an unfavorable interaction of the methine hydrogen with Thr40 for the slow enantiomer and from subtle differences in the orientations of the other three substituents. This success in rationalizing the enantioselectivity supports the notion that an umbrella-like-inversion orientation can contribute to enantioselectivity in lipases.

Nucleophile-dependent regioselective ring opening of 2-substituted N,N-dibenzylaziridinium ions: bromide versus hydride.

The ring opening of 2-substituted N,N-dibenzylaziridinium ions by bromide exclusively occurs at the substituted aziridine carbon atom in a stereospecific way, whereas the opposite regioselectivity was observed for hydride-induced ring opening at the unsubstituted position; furthermore, this unprecedented hydride-promoted reactivity was validated by means of Density Functional Theory (DFT) calculations.

The preparation of stable aziridinium ions and their ring-openings.

The reaction of enantiomerically pure 2-substituted 1-phenylethyl-aziridine with methyl trifluoromethanesulfonate generated a stable methylaziridinium ion, which was reacted with various external nucleophiles, including nitrile, to yield synthetically valuable and optically pure acyclic amine derivatives in a completely regio- and stereoselective manner.

Aminostyrylbenzofuran derivatives as potent inhibitors for Abeta fibril formation.

The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a-w and their inhibitory activities for Abeta fibril formation were described. All the synthesized compounds were evaluated by thioflavin T (ThT) assay and displayed potent inhibitory activities for Abeta fibril formation. Among them, compounds 1i and 1q exhibited excellent inhibitory activities (IC(50)=0.07 and 0.08 microM, respectively) than those of Curcumin (IC(50)=0.80 microM) and IMSB (IC(50)=8.00 microM) as reference compounds. Both compounds were selected as promising candidates for further biological evaluation.

High prevalence of cognitive impairment among students near mount Merapi: a case study.

This descriptive, cross-sectional study illustrates the high prevalence of intellectual impairment among students at the Kanisius Prontakan primary school near Mt. Merapi, one of the most active volcanic mountains in Indonesia. To determine the possible cause of these abnormal cognitive impairments, we considered and investigated the threats to society and the environment of the frequent volcanic eruptions, as well as the effects of malnutrition due to extreme poverty, in that area. The results showed that intellectual impairment and stunting were remarkably common among the students, with 10.7% of the students showing sigma of intellectual impairment and 96.4% showing signs of stunting. No noticeable chemical problems due to the volcanic activity were found in the drinking water, and no causes of such disorders other than poor nutrition due to poverty were found. Nevertheless, our results provide information on the high prevalence of health problems being experienced by children living in one of the most isolated and underdeveloped volcano mountain areas in Indonesia and draws attention to the severe effects of malnutrition on the development of those children.

Dihydroxylation of 2-vinylaziridine: efficient synthesis of D-ribo-phytosphingosine.

An efficient and highly stereoselective synthesis of D-ribo-(2S,3S,4R)-phytosphingosine was accomplished in 62% overall yield starting from commercially available (2S)-hydroxymethylaziridine via osmium-catalyzed asymmetric dihydroxylation as a key step.

Sphingosine 1-phosphate (S1P) induces shape change in rat C6 glioma cells through the S1P2 receptor: development of an agonist for S1P receptors.

Treatment with isoprenaline led to a change in the cell morphology of rat C6 glioma cells. This morphological change was reverted by the addition of sphingosine 1-phosphate (S1P). Using this morphological change as a response marker we determined that DS-SG-44 ((2S,3R)-2-amino-3-hydroxy-4-(4-octylphenyl)butyl phosphoric acid) was an agonist of S1P receptors. The DS-SG-44-induced morphological reversion was not observed with such structurally related molecules as DS-SG-45 ((2S,3R)-2-amino-3-hydroxy-4-(3-octylphenyl)butyl phosphoric acid) and DS-SG-12 ((2S,3R)-2-amino-4-(4-octylphenyl)butane-1,3-diol). The S1P- and DS-SG-44-induced shape changes were neither reproduced with the S1P1/S1P3 receptor agonist VPC24191 nor inhibited by the S1P1/S1P3 receptor antagonist, VPC23019. Transfection with small interfering RNA (siRNA) for the S1P2 receptor greatly inhibited the DS-SG-44-induced shape change, and in part an S1P-induced response. In the presence of VPC23019, siRNA transfection for the S1P2 receptor almost completely blocked the S1P- and DS-SG-44-induced shape changes. Our results suggested that DS-SG-44, a newly-synthesized S1P analogue, acted as an S1P receptor agonist and that the S1P-induced shape change in rat C6 glioma cells was mediated mainly through the S1P2 receptor, and cooperatively through the S1P1/S1P3 receptors.

Lewis acid-catalyzed stereospecific ring expansion of aziridine-2-carboxylates to imidazolidin-2-ones.

Lewis acid-catalyzed ring expansion reaction of chiral aziridine-2-carboxylate proceeds regio- and stereospecifically to yield enantiomerically pure 4-functionalized imidazolidin-2-ones in high yields.

Efficient Synthesis of Ephedra Alkaloid Analogues Using an Enantiomerically Pure N-[(R)-(+)-alpha-Methylbenzyl]aziridine-2-carboxaldehyde.

Efficient preparation of enantiomerically pure (2S)-aziridine-2-carboxaldehyde 9 and its 2(R) isomer and highly diastereoselective addition of organolithium reagents to the aldehyde 9 are described. The diastereoselectivity in additions of the lithium reagents seems to come from "chelation-controlled" carbon-carbon bond formation and is influenced by the source of the organometallic compound, solvent, and the presence of a Li salt. The C(3)-N bond of the aziridine ring of the addition products was regioselectively reduced by catalytic hydrogenation in the presence of Pearlman's catalyst to provide enantiomerically pure 1,2-amino alcohols. The absolute stereochemistries of the amino alcohol 13a were assigned as (1S,2S) when the C-1 substituent was phenyl by comparison with those of commercially available norpseudoephedrine.

Alkylative ring opening of N-methylaziridinium ions and a formal synthesis of tyroscherin.

Alkylative ring-opening reactions of stable 2-substituted N-methylaziridinium ions proceeded with various alkyl- or arylmagnesium bromides in the presence of CuI to yield synthetically valuable and optically pure alkylated acyclic amines in a completely regio- and stereoselective manner. This was applied to a formal synthesis of the cytotoxic natural product tyroscherin.

Synthesis of 2,5-disubstituted 6-azaindoles from substituted aziridines via intramolecular cyclization.

A new and efficient preparation of pharmacologically and biologically important 2,5-disubstituted 6-azaindoles was achieved from cyclizations of aziridin-2-yl dipropargylic alcohols as adducts of two propargyl groups to ethyl 1-benzylaziridine-2-carboxylate. The sequential cyclizations include pyrrole formation and a novel base-catalyzed intramolecular acetylenic Schmidt reaction.