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Conversion of chiral N-acyl-4-benzyl-oxazolidinones (I) to titanium enolates and subsequent quenching with TEMPO results in an efficient formation of 2-aminoxylation adducts in excellent yields and good enantioselectivities.

[reaction: see text] Lewis acid mediated addition of chiral titanium enolates to glycals provides either alpha- or beta-1'-methyl-substituted C-glycosides. This highly stereoselective methodology permits the modular preparation of three of the four possible diastereomers.

Chx 2 BCl-mediated syn -aldol reaction of the α-OTBS lactate-derived ketone 1 followed by in situ reduction of the resulting boron aldolate with LiBH 4 lead to complete stereoselectivity for the boronates 2 in 80–95% yields. Then, a very mild oxidative work-up of 2 (H 2 O 2 /NaOAc in THF–H 2 O) allows isolation of syn , syn -2-methyl-1,3-diols 3 in yields up to 95% without migration of the TBS group.

The Negishi coupling between a chiral C3 synthon and an iodoalkene arising from 3-butyn-1-ol, which gave the C3–C9 fragment of amphidinolide Y, was the starting point of a formal total synthesis of this marine natural product. By means of Sharpless ADH and TADDOL-mediated crotylation, the full western fragment (C1–C11) was obtained, which was coupled with the eastern fragment (3-hydroxyoxolane derivative). The penultimate step (ring-closing metathesis, with G-II, H–G-II, or Nitro-Grela reagents, under several conditions) posed great difficulties. The cyclization was achieved with 15c (7,9-bis- O -TES) and 15d (7- O -TES, 9- O -TBS); more than stoichiometric amounts of the H–G-II Ru complex were required for complete conversion.

4-Pyridinecarboxaldehyde Dichloromethane 3-tert-Butyl-2-hydroxybenzaldehyde Sodium borohydride Methanol 2-(1,1-Dimethylethyl)-6-[[[(1R,2R)-2-[(4-pyridinylmethyl)amino]-cyclohexyl]amino]methyl]-phenol (1R,2R)-1,2-Diaminocyclohexane (1S)-1-(4-Nitrophenyl)-2-nitroethane-1-ol Copper acetate Ethanol p-Nitrobenzaldehyde Nitromethane Keywords: Nitroaldol; Henry reaction; p-Nitrobenzaldehyde; Nitromethane; Copper (II) complex; (R,R)-1,2-diaminocyclohexane; (1S)-1-(4-nitrophenyl)-2-nitroethane-1-ol; Aromatic aldehyde; Aliphatic aldehyde

N -Nosyl aziridines can be easily prepared from 1,2-amino alcohols derived from α-amino acids. Nucleophilic ring-opening of N -nosyl aziridines with cyanide ions followed by hydrolysis of the corresponding nitriles lead to N -nosyl β 3 -amino acids, which can be readily converted into a variety of derivatives bearing adequate functionality for peptide synthesis. The proposed methodology is simple, efficient, and amenable to large-scale preparations.

A practical solution to the problem of converting directly 1,2-azido alcohols to Boc-amino alcohols, without recourse to catalytic hydrogenation, involves the use of Me3P/Boc2O in THF (or CH2Cl2) and aqueous NaOH at rt (90–98% yields). The same azido alcohols can be converted in one-pot to the corresponding oxazolidinones with Boc2O/DMAP/Me3P or even better with CO2 and Me3P under basic catalysis (91–96% yields).

An N,N-disubstituted cyclo-β3-tetrapeptide, identified as a potential molecular scaffold, has been synthesised on a multigram scale from β-homophenylalanine by employing a nosylate-based protection strategy. C2-Symmetric derivatives containing pseudoaxial, combinatorially addressable functionalities have been prepared from the parent cyclopeptide.

[reaction: see text]Comprehensive analysis of the enolization of alpha-silyloxyketones by Chx2BCl/R3N has allowed us to design stereoselective Chx2BCl-mediated aldol processes that afford syn or anti aldol products and to disclose a hypothesis that accounts for the subtle effects that determine their enolization.

The same precursor-namely, (2R)-2-ethyl-4-penten-1-ol-was used to obtain fragments C9-C13 and C1-C8 of 1, the aglycon of Sch 38516 (which is active against Candida sp.) and fluvirucin B(1) (which is active against influenza A virus). The key steps of the synthesis were the aldol-like reaction between the two fragments and the macrolactamization of a 13-azidotridecanoic acid derivative (see scheme). MOM=methoxymethyl, Py=2-pyridyl.

Aldol reactions between the putative Z-enolate derived from 2-methyl-3-pentanone and several chiral α-tert-butyldiphenylsilyloxy aldehydes have been studied. The stereochemical outcome suggests that stereoelectronic effects play a dominant role in these reactions and the results can be accommodated by the Felkin model, with gauche pentane interactions being less important.

Titanium-mediated aldol reactions of 1 and ( S )-2- tert -butyldiphenylsilyloxy aldehydes ( matched pair ) afford syn Felkin diastereomers in excellent yield and absolute stereochemical control. Having established that chain length does not affect the yield of the titanium aldol reactions we have been able to achieve short, high yielding and enantioselective syntheses of NFX-2 and Antimycinone.

N -Substituted tetralactams (cyclo-β-tetrapeptides) have been identified as potential molecular scaffolds by computer-aided design; compound 2 , arising from l -β-homophenylalanine, has been prepared as a model system and its structure elucidated by single crystal X-ray analysis and NMR spectroscopy.

Good levels of 1,4- anti asymmetric induction are obtained in the TiCl 3 ( i -PrO)-mediated aldol reaction of α-benzyloxy methyl ketones with achiral aldehydes. Such methodology represents a new approach to the substrate-controlled acetate aldol reaction, which can be useful to design more efficient synthesis.

Stereoselectivity of TiCl4-mediated aldol reactions from (S)-2-benzyloxy-3-pentanone is dramatically improved when the reaction is carried out in the presence of 1.1 equiv of tetrahydrofuran (THF) or 1,2-dimethoxyethane (DME). The resultant 2,4-syn-4,5-syn adducts are then obtained in diastereomeric ratios up to 97:3, which proves that the appropriate choice of the Lewis acid (TiCl4-THF or DME vs Ti(i-PrO)Cl3) engaged in the process permits access to both syn-aldol adducts.

A highly efficient and straightforward aminoxylation of titanium(IV) enolates from (S)-N-acyl-4-benzyl-5,5-dimethyl-1,3-oxazolidin-2-ones with TEMPO has been developed. A wide array of functional groups on the acyl moiety, including alkyl and aryl substituents, olefins, esters, or a-cyclopropyl, as well as a-trifluoromethyl groups, are well tolerated. This transformation can therefore produce the a-aminoxylated adducts in excellent yields with high diastereomeric ratios (d.r.). In turn, parallel additions to the a,b-unsaturated N-acyl counterparts give the corresponding g-adducts with complete regioselectivity in moderate to good yields. Removal of the piperidinyl moiety or the chiral auxiliary converts the resultant adducts into enantiomerically pure a-hydroxy carboxyl derivatives, alcohols, or esters in high yields under mild conditions. Finally, a new mechanistic model based on the biradical character of the titanium(IV) enolates has been proposed.

Substrate-controlled Michael additions of the titanium-(IV) enolate of lactate-derived ketone 1 to acyclic α,β-unsaturated ketones in the presence of a Lewis acid (TiCl4 or SnCl4) provide the corresponding 2,4-anti-4,5-anti dicarbonyl compounds in good yields and excellent diastereomeric ratios. Likely, the nucleophilic species involved in such additions are bimetallic enolates that may add to enones through cyclic transition states. Finally, further studies indicate that a structurally related β-benzyloxy chiral ketone can also participate in such stereocontrolled conjugate additions.

Amides derived from pyrrolidine and methyl ( S )-lactate, methyl ( S )-2-hydroxy-3-phenylpropanoate, or methyl ( S )-2-hydroxy-3-methylbutanoate, after O -benzylation and O -silylation have been treated with EtLi or EtMgCl under suitable conditions, to give excellent overall yields of enantiopure ethyl ketones. The chelating ability of α-OBn amides (and even of α-O-TBS amides, which has been demonstrated by NMR to be better than that of N -OMe amides) accounts for the performance of the approach.

Aldol-like reactions of titanium enolates derived from α-OH, α-OBn, and α-OTBS ketones with a series of aldehydes have been studied. In sharp contrast to the O-benzyl derivatives, the TBS-protected ketones lead to excellent yields and selectivities ( syn-syn anti-syn ratios from 30:1 to >95:1) even for the lactate-derived substrate (2-tert-butyldimethylsilyloxy-3-pentanone).

A novel substrate-controlled aldol reaction of a chiral isopropyl ketone is reported. The outstanding regioselective enolization by TiCl4–i-Pr2NEt provides a chelated enolate that can participate in highly diastereoselective additions to a wide array of aldehydes favouring the corresponding 2,5-syn adducts.

The titanium-mediated aldol reaction of chiral ketones is sensitive to the titanium Lewis acid used in the enolization step and represents a new approach to the substrate-controlled acetate aldol reaction.

Asymmetric aldol-like reactions of cinnamaldehyde, dienal 3 (fragment C7-C12 of macrolactin A), and dienal 4 (fragment C15-C24) with (i) chiral acetylthiazolidinethione-derived enolates, (ii) chiral boron enolates, and (iii) silyl enolates in the presence of chiral titanium-2,2′-dinaphthol complexes are compared. Use of the thiazolidinethione auxiliary and TiCl 4 shows practical advantages; e.g., C5-C12 fragment 7 has been isolated enantiomerically pure in 74% yield.

The stereoselective outcome of the title reaction is found to depend on the nature of the O-protecting group of glycolate substrate.

Oxidized poly(2,5-di-(-2-thienyl)-pyrrole was synthesized electrochemically from a 5 to 20 mM monomeric solution in 0.1 M LiClO 4 + acetonitrile (ACN). The electrochemical behaviour of films was studied in 0.1 M LiClO 4 aqueous solution, where an insoluble reduced form was found. Solubilities of both oxidized and reduced states were determined in DMSO, acetone and ACN. Their densities and electrical conductivities were also obtained. The solubility of the reduced form is about 15 times higher in DMSO and ACN than that of the oxidized form. The oxidized polymer is insoluble in ACN solutions of perchlorate salts. The high solubility of the reduced state in this medium allows a quantitative electrodissolution of the polymer following the reduction process. Results from electrochemical experiments, ultramicrogravimetry and elemental analysis indicate an average presence of 0.65 ClO 4 − ions per monomeric unit incorporated in the oxidized polymer. Both states contain soluble oligomers with from two to six monomeric units, as detected by mass spectrometry (fast atom bombardment). The molecular mass of these oligomers indicates a loss of two protons per monomer incorporated in the polymer, in agreement with an electropolymerization mechanism involving polycondensation of radicals.

New syntheses of densely functionalized protected derivatives of 3-amino-3,6-dideoxyaminosugars have been accomplished in an efficient and straightforward manner. The key step of such approaches involves a highly stereoselective titanium-mediated aldol addition of a chiral α-bromo ketone, easily available from lactate esters, to crotonaldehyde. Further functional group transformations, including a new regioselective Staudinger–aza-Wittig reaction of an azidodiacetate, afford in a few steps and high yield the desired carbohydrates as advanced intermediates capable of participating in subsequent glycosylation reactions.

Substrate-controlled titanium-mediated aldol reactions from (S)-4-benzyloxy-3-methyl-2-butanone provide satisfactory levels of 2,5-syn asymmetric induction if they are carried out in the presence o...

The influence of substitution pattern of α-siloxy ketones on the reactivity in Ti-mediated aldol reactions is studied.

This review deals with stereoselective acetate aldol reactions mediated by metal enolates. It summarizes recent advances in aldol additions of unsubstituted metal enolates that either incorporate chiral auxiliaries, stoichiometric Lewis acids, or catalytic Lewis acids or bases, or act in substrate-controlled reactions. These approaches provide stereocontrolled aldol transformations that allow the efficient synthesis of structurally complex natural products.

A substrate-controlled synthesis of (+)-herboxidiene from two lactate-derived chiral ketones is described. Remarkably, most of the carbon backbone was constructed through highly stereoselective titanium-mediated aldol reactions and an Ireland–Claisen rearrangement. Furthermore, an oxa-Michael cyclization and a high-yield Suzuki coupling were used to assemble the pyran ring and the diene moiety respectively.

This review deals with stereoselective acetate aldol reactions mediated by metal enolates. It summarizes recent advances in aldol additions of unsubstituted metal enolates that either incorporate chiral auxiliaries, stoichiometric Lewis acids, or catalytic Lewis acids or bases, or act in substrate-controlled reactions. These approaches provide stereocontrolled aldol transformations that allow the efficient synthesis of structurally complex natural products.

4 páginas, 5 figuras, 1 tabla -- PAGS nros. 1027-1030, Microtubules and actin filaments play important biological roles in mitosis, cytokinesis, cell signaling, intracellular transport, and cell motility of eukaryotic cells.1, 2 Molecules that target these cytoskeleton proteins are potential antitumor3 or anti-HIV agents.4 In fact, there are several clinical drugs that target the stabilization (paclitaxel-like behavior) or destabilization (vinca-like or colchicine-like behavior) of microtubules, specifically their heterodimeric component, α,β-tubulin.3 On the other hand, no actin-targeting drug has yet entered clinical studies. Amphidinolides are a series of structurally dissimilar cytotoxic macrolides isolated from dinoflagellates (Amphidinium sp.).5–7 Their mechanisms of action are unknown, except that for one that has one of the largest rings, the 26-membered macrolide amphidinolide H (Amp-H, MW=562.73); this shows cytotoxicity in the nanomolar range against several carcinoma cell lines.8 Amp-H drastically and irreversibly deformed actin fibers;9 the actin fibers completely disappeared, and only a few disorganized aggregates remained in the cells. Amp-H induced multinucleated cells by disrupting actin organization (polyploid cells). In vitro assays on purified actin indicated that Amp-H stimulates actin polymerization, and stabilizes the actin filaments (F-actin).10, 11 In contrast, most of the smallest amphidinolides are cytotoxic in the micromolar range. For example, amphidinolide X (1, MW=448.59)12 and amphidinolide J (4, MW=390.56)13 have IC50 values of 1.3 and 6.9 μM, respectively, against the lymphocytic leukemia cell line L1210,12–14 although their mechanisms of action have not been reported. As these small amphidinolides are easier to synthesize than the larger molecules,15, 16 it would be desirable to identify their binding sites. Appropriate chemical modifications of these natural products might afford leads with activities below 0.1 μM that might eventually give rise to new antitumor agents. We report here biological studies of 1, the structurally related synthetic diolides 2 and 3, and 4 (Scheme 1). We examined their effect on the proliferation of A2780 (human ovarian carcinoma) and of LoVo (human colon carcinoma) cell lines, as well as on the cytoskeleton proteins tubulin, actin, and intermediate filaments in A549 (lung carcinoma) and PtK2 cells. Their effects on actin polymerization was then studied in vitro, MICINN (Spanish Government) is acknowledged for grants BIO2010-16 351 (to J.F.D.), and CTQ 2009-13590 (to J.V.). M.B. thanks GlaxoSmithKline and the CNRS for a BDI grant. J.V. also thanks the Generalitat of Catalunya for a gift (2009SGR825). O.P. thanks the Fundació Cellex de Barcelona for a postdoctoral fellowship (May 2009–June 2010)

ω-Azido acids, after activation of the carboxyl groups as mixed anhydrides, N3(CH2)nCOOCOAr (Ar = 3,5-dinitrophenyl or 2,4,6-trichlorophenyl), can be converted to macrolactams in good yields by treatment with Bu3P under high-dilution conditions; the presence of 4-dimethylaminopyridine improves slightly the yields. Amides and peptides can be readily obtained by this procedure.

Lewis acid-mediated reaction of the titanium enolate arising from ( S )- N -acetyl-4-isopropyl-1,3-thiazolidine-2-thione with dimethyl acetals furnishes β-methoxy carboxyl adducts in good yields and stereoselectivities. The adducts can be, in turn, transformed into a wide range of enantiopure α-unsubstituted β-methoxy carboxyl derivatives in excellent yields.

[reaction: see text] High stereoselectivities (up to 98% de) have been achieved for the Lewis acid-mediated cross-coupling reaction of dimethyl acetals to a chiral 1,3-thiazolidine-2-thione-derived titanium enolate. The reaction affords enantiopure anti alpha-methyl-beta-alkoxy carbonyl compounds in a wide range of acetals.

A sequential transformation based on a titanium-mediated aldol reaction from chiral α-tert-butyldimethylsilyloxy ketones followed by reduction of the resultant aldolates with LiBH4 provides a straightforward access to syn-1,3-diols. These diols, containing up to three new stereocentres, can be easily isolated in high yields after a simple work-up without any additional oxidative treatment, which confers to this procedure an appealing position to prepare stereoselectively such sort of structures.

Amides derived from pyrrolidine and methyl ( S )-lactate, methyl ( S )-2-hydroxy-3-phenylpropanoate, or methyl ( S )-2-hydroxy-3-methylbutanoate, after O -benzylation and O -silylation have been treated with EtLi or EtMgCl under suitable conditions, to give excellent overall yields of enantiopure ethyl ketones. The chelating ability of α-OBn amides (and even of α-O-TBS amides, which has been demonstrated by NMR to be better than that of N -OMe amides) accounts for the performance of the approach.

Aldol-like reactions of titanium enolates derived from α-OH, α-OBn, and α-OTBS ketones with a series of aldehydes have been studied. In sharp contrast to the O-benzyl derivatives, the TBS-protected ketones lead to excellent yields and selectivities ( syn-syn anti-syn ratios from 30:1 to >95:1) even for the lactate-derived substrate (2-tert-butyldimethylsilyloxy-3-pentanone).

Morpholine-derived amides react with RMgX to give the corresponding ketones in good yield. The mild conditions required and low cost of starting materials make this method very appealing for large scale preparations.

Asymmetric syntheses of the C-1 alkyl side chains of Zaragozic acids A and C from a common chiral precursor 4 are reported. The stereoselective reduction of unsaturated ketones 8 and 10 is the key step of both syntheses.

Reaction of azides with trimethylphosphine followed by addition of 2-(tert-butoxycarbonyloxyimino)-2-phenyl-acetonitrile (Boc-ON) at −20 °C and stirring at r.t. for 5 h affords the desired Boc-amines in 87–100% yields. Similar yields are obtained by mixing all components together (azide, Me3P, and Boc-ON) in toluene or THF.

Titanium-mediated aldol reactions of 1 and ( S )-2- tert -butyldiphenylsilyloxy aldehydes ( matched pair ) afford syn Felkin diastereomers in excellent yield and absolute stereochemical control. Having established that chain length does not affect the yield of the titanium aldol reactions we have been able to achieve short, high yielding and enantioselective syntheses of NFX-2 and Antimycinone.

Aldol reactions between the putative Z-enolate derived from 2-methyl-3-pentanone and several chiral α-tert-butyldiphenylsilyloxy aldehydes have been studied. The stereochemical outcome suggests that stereoelectronic effects play a dominant role in these reactions and the results can be accommodated by the Felkin model, with gauche pentane interactions being less important.

A practical procedure for the direct conversion of azides to carbamates has been found. High yields are obtained when primary and secondary aliphatic azides, as well as α-azido esters, are treated in THF with Me 3 P and several chloroformates (ClCOOBn, ClCOOMe, ClCOOEt, ClCOOCH 2 CCl 3 , ClCOOCH 2 CHCH 2 ).