Stereoselective Synthesis of Microcarpalide
The first total synthesis of the naturally occurring nonenolide, microcarpalide, is described. The key step in the synthesis was the ring-closing metathesis of a dienic ester prepared in turn by coupling an acid and an alcohol stereoselectively synthesized from (S,S)-tartaric acid and (R)-glycidol, respectively. [structure: see text]
Synthesis and biological evaluation of cyclic derivatives of combretastatin A-4 containing group 14 elements
Several tricyclic compounds inspired by the structure of combretastatin A-4 and bearing group 14 elements have been synthesized by homocoupling lithiated aryl fragments followed by ring-closing metathesis. These tricyclic compounds and their diolefin precursors were evaluated for their antiproliferative action on the tumor cell lines HT-29, MCF-7, HeLa and A-549 and on the non-tumor cell line HEK-293. In addition, their effects on the cell cycle were also measured. The tricyclic compounds show antiproliferative activity similar to that of combretastatin A-4, even though they are not so active in arresting the cell cycle. However, some diolefin precursors are able to cause accumulation of ce…
Stereoselective synthesis of the naturally occurring 2-pyranone dodoneine
The first total synthesis of the naturally occurring dihydropyranone dodoneine is reported. Asymmetric allylation reactions were used for the stereoselective generation of the two stereogenic centers. The pyranone ring was created by ring-closing metathesis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Stereoselective Synthesis of the Antiprotozoal Lactone Passifloricin A and Seven Isomers Thereof
The conjugated delta-lactone passifloricin A, a natural product with antiprotozoal activity, and seven isomers thereof have been synthesized in enantiopure form. It has been shown in this way that the proposed structure for the natural compound was erroneous. The correct structure is now evidenced. Key steps of the syntheses were asymmetric Brown-type aldehyde allylations and ring-closing metatheses.
The high affinity dopamine uptake inhibitor, JHW 007, blocks cocaine-induced reward, locomotor stimulation and sensitization
The discovery and evaluation of high affinity dopamine transport inhibitors with low abuse liability is an important step toward the development of efficacious medications for cocaine addiction. We examined in mice the behavioural effects of (N-(n-butyl)-3Ά-[bis(4Ά-fluorophenyl)methoxy]-tropane) (JHW 007), a benztropine (BZT) analogue that blocks dopamine uptake, and assessed its potential to influence the actions of cocaine in clinically-relevant models of cocaine addiction. In the conditioned place preference (CPP) paradigm, JHW 007 exposure did not produce place conditioning within an ample dose range but effectively blocked the CPP induced by cocaine administration. Similarly, in the CP…
Stereoselective synthesis of the published structure of feigrisolide A. Structural revision of feigrisolides A and B.
The total synthesis of the proposed structure of feigrisolide A is reported. Ethyl (S)-3-hydroxybutyrate was the chiral starting material. A Brown asymmetric allylation and an Evans aldol reaction were key steps of the synthesis. The NMR data of the synthetic product are different from those of the natural product. The published structure of feigrisolide A is therefore erroneous. A subsequent comparison of spectral data strongly suggests that feigrisolides A and B are identical with (-)-nonactic acid and (+)-homononactic acid, respectively.
ChemInform Abstract: Diastereoselectivity in Organometallic Additions to the Carbonyl Group of Protected Erythrulose Derivatives.
We have investigated a number of nucleophillic additions to l-erythrulose derivatives (4−12) bearing protective O-silyl, O-benzyl, and O-trityl groups in various relative positions. The results are discussed in the frame of chelated vs nonchelated transition states with additional support of previously published theoretical calculations. Sound evidence appears to exist for the formation of α-chelates as the key intermediates in nucleophillic additions to these α,β-dioxygenated ketones. Since such evidence is still lacking in the case of β-chelates, proposals of their intermediacy have been relegated in favor of the more solid Felkin−Anh model, which predicts the same stereochemical result. …
ChemInform Abstract: Stereoselective Synthesis of syn-α-Methyl-β-hydroxy Esters.
Abstract Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2- syn /1,3- syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O -formylated syn -α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.
Stereoselective synthesis of the published structure of synargentolide A and of one of its stereoisomers
A stereoselective synthesis is described of the structure published for the naturally occurring synargentolide A, an α,β-unsaturated lactone. The key steps of the synthesis were a Brown´s asymmetric allylation and a ring closing metathesis. The spectroscopic data of the synthetic product were very close to those of the natural product but did not exactly match them. An epimer of the published structure was then synthesized according to a similar strategy. Again, the data of the synthetic product did not match those reported for the natural product. It is thus likely that the actual structure of synargentolide A differs from the published one in more than mere stereochemical aspects. Marco V…
The atypical dopamine transport inhibitor, JHW 007, prevents amphetamine-induced sensitization and synaptic reorganization within the nucleus accumbens
Benztropine (BZT) analogs, a family of agents with high affinity for the dopamine transporter have been postulated as potential treatments in stimulant abuse due to their ability to attenuate a wide range of effects evoked by psychomotor stimulants such as cocaine and amphetamine (AMPH). Repeating administration of drugs, including stimulants, can result in behavioral sensitization, a progressive increase in their psychomotor activating effects. We examined in mice the sensitizing effects and the neuroplasticity changes elicited by chronic AMPH exposure, and the modulation of these effects by the BZT derivative and atypical dopamine uptake inhibitor, JHW007, a candidate medication for stimu…
Aldol Reactions with Erythrulose Derivatives: Stereoselective Synthesis of Differentially Protected syn -α,β-Dihydroxy Esters
Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown's chloro-dicyclohexylborane/tertiary amine system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2-syn/1,3-syn stereoisomer. Through oxidative cleavage of the aldol adducts with periodic acid hydrate, enantiopure syn-α,β-dihydroxy esters with either hydroxyl group differently protected have been prepared. These erythrulose derivatives therefore behave as a chiral hydroxy acetate (glycolate) enolate equivalent.
Synthesis of (±)-(E)-2,6-dimethyl-6-hydroxyocta-2,7-dienoic acid and the corresponding amide (“acacialactam”)
Abstract The total synthesis of the title compounds in racemic form is described. Linalool was used as the starting material and transformed into the target molecules in 6 steps. The synthetic amide displays spectral properties identical to those reported for the natural compound acacialactam, indicating that the structure proposed for the latter compound is not correct.
Boron aldol additions with erythrulose derivatives: dependence of stereoselectivity on the type of protecting group
Abstract Boron aldol additions of 1- O -silylated 3,4-di- O -benzyl- and 3,4-di- O -benzoyl- l -erythrulose and achiral aldehydes using dicyclohexylboron chloride have been investigated. The dibenzyl derivative gave syn/syn stereoisomers with high stereoselectivity, whereas the dibenzoyl derivative gave syn/anti stereoisomers. It is believed that, while the dibenzoyl erythrulose gives rise to the E enolate in the presence of dicyclohexylboron chloride, as usually observed with this reagent, only the Z enolate is formed in the case of the dibenzyl derivative.
ChemInform Abstract: Aldol Reactions with Erythrulose Derivatives: Stereoselective Synthesis of Differentially Protected syn-α,β-Dihydroxy Esters.
Boron enolates of 1-O-silylated erythrulose 3,4-acetonides prepared with Brown's chloro-dicyclohexylborane/tertiary amine system have been shown to react with achiral aldehydes in a highly stereoselective way to yield a 1,2-syn/1,3-syn stereoisomer. Through oxidative cleavage of the aldol adducts with periodic acid hydrate, enantiopure syn-α,β-dihydroxy esters with either hydroxyl group differently protected have been prepared. These erythrulose derivatives therefore behave as a chiral hydroxy acetate (glycolate) enolate equivalent.
Arylpyridines, arylpyrimidines and related compounds as potential modulator agents of the VEGF, hTERT and c-Myc oncogenes.
Twenty-four derivatives structurally related to honokiol have been synthesized and biologically evaluated. IC50 values were determined towards the HT-29, MCF-7 and HEK-293 cell lines. Some of these derivatives exhibited comparable or lower IC50 values than honokiol towards the HT-29 and MCF-7 cell lines or else higher selectivity indexes than the natural product. Twelve selected derivatives were evaluated for their ability to inhibit the expression of the VEGFA, hTERT and c-Myc genes and also to inhibit the production of total c-Myc protein and the secretion of the VEGF protein. One of the most promising compounds, 3-(2,4-dimethoxyphenyl)pyridine, may be a good candidate for further studies…
Stereoselective synthesis and determination of the cytotoxic properties of spicigerolide and three of its stereoisomers.
Stereoselective syntheses of the naturally occurring, cytotoxic lactone spicigerolide and three nonnatural stereoisomers thereof are described. The commercially available sugar l-rhamnose was in all cases the chiral starting material. Key steps in each of these syntheses were asymmetric Brown allylations and ring-closing metatheses. The cytotoxic activities of the four lactones against a range of tumoral lines were then determined.
Stereoselective synthesis of syn-α-methyl-β-hydroxy esters
Abstract Boron enolates of an ethyl ketone structurally related to erythrulose react with achiral aldehydes in a highly stereoselective fashion to yield 1,2- syn /1,3- syn stereoisomers. Oxidative cleavage of the aldol adducts yields enantiopure O -formylated syn -α-methyl-β-hydroxy esters, easily cleaved to the corresponding hydroxyl-free compounds. The aforementioned ketone behaves therefore as a chiral propionate enolate equivalent.
Stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A.
A stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A has been performed. The preparation of a cis-2,6-disubstituted tetrahydropyran ring via stereoselective reduction of an intermediate cyclic hemiacetal was one key feature of the synthesis. The macrocyclic lactone ring was created by means of a ring-closing metathesis (RCM), whereby the new C=C bond displayed exclusively the undesired Z configuration. Conversion to the required E configuration was achieved via photochemical isomerization.
Stereoselective synthesis of the naturally occurring styryllactones (+)-goniofufurone and (+)-cardiobutanolide.
The naturally occurring gamma-lactones (+)-goniofufurone 1 and (+)-cardiobutanolide 2, two pharmacologically active products from Goniothalamus species (Annonaceae), have been synthesized in enantiopure form using l-erythrulose as the chiral starting material. Key steps of these syntheses were a stereoselective anti boron aldol reaction and an asymmetric allylboration.
Stereoselective anti aldol reactions of erythrulose derivatives. Functionalized chiral d3 and d4 synthons.
An improved procedure for the synthesis of anti aldols from protected erythrulose derivatives is reported. The preparation of functionalized d3 and d4 synthons with various stereochemical arrays by means of this methodology is described and subsequently applied to a stereoselective formal synthesis of the natural metabolite goniothalesdiol.
ChemInform Abstract: Boron Aldol Additions with Erythrulose Derivatives: Dependence of Stereoselectivity on the Type of Protecting Group.
Abstract Boron aldol additions of 1- O -silylated 3,4-di- O -benzyl- and 3,4-di- O -benzoyl- l -erythrulose and achiral aldehydes using dicyclohexylboron chloride have been investigated. The dibenzyl derivative gave syn/syn stereoisomers with high stereoselectivity, whereas the dibenzoyl derivative gave syn/anti stereoisomers. It is believed that, while the dibenzoyl erythrulose gives rise to the E enolate in the presence of dicyclohexylboron chloride, as usually observed with this reagent, only the Z enolate is formed in the case of the dibenzyl derivative.
The dopamine uptake inhibitor 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane reduces cocaine-induced early-gene expression, locomotor activity, and conditioned reward.
Benztropine (BZT) analogs, a family of high-affinity dopamine transporter ligands, are molecules that exhibit pharmacological and behavioral characteristics predictive of significant therapeutic potential in cocaine addiction. Here, we examined in mice the effects of 3 alpha-[bis(4'-fluorophenyl)metoxy]-tropane (AHN-1055) on motor activity, conditioned place preference (CPP) and c-Fos expression in the striatum. AHN-1055 produced mild attenuation of spontaneous locomotor activity at a low dose (1 mg/kg) and weak stimulation at a higher dose (10 mg/kg). In parallel, the BZT analog significantly increased c-Fos expression in the dorsolateral caudoputamen at the high dose, whereas producing ma…
Stereoselective Synthesis of the Cytotoxic Macrolide FD-891
[reaction: see text] A total synthesis of the naturally occurring, cytotoxic macrolide FD-891 is described. Three fragments were first stereoselectively constructed using mainly asymmetric aldol and allylation reactions. The complete framework was then assembled using two Julia-Kocienski olefinations to connect the three fragments and a Yamaguchi reaction to close the macrolactone ring.
Synthesis and Biological Evaluation of α-Tubulin-Binding Pironetin Analogues with Enhanced Lipophilicity
Financial support has been granted to M. C. by the Spanish Ministry of Education and Science (project numbers CTQ2008-02800 and CTQ2011-27560), by the Conselleria d'Empresa, Universitat i Ciencia de la Generalitat Valenciana (ACOMP09/113) and by the BANCAJA-UJI Foundation (P1-1B2002-06, P1-1B-2008-14 and PI-1B2011-37). The biological work has been supported in part by grants from the Spanish Ministry of Education and Science (grant number BIO2010-16351) and from the Comunidad de Madrid (grant number S2010/BMD-2457 BIPEDD2-CM), both to J. F. D. We further thank the Matadero Municipal Vicente de Lucas in Segovia for providing the calf brains, which were the source of tubulin.
New generation of cancer stem cells inhibitors in non-small cell lung cancer.
e20545Background: Lung cancer is the commonest tumor worldwide of which the most frequent type is non-small cell lung cancer (NSCLC) that represents a large proportion of cancer deaths and is chara...
Stereoselective Syntheses of Naturally Occurring 5,6-Dihydropyran-2-ones
The published syntheses of naturally occurring 5,6-dihydropyran-2-ones are reviewed. Figure options Download full-size image Download as PowerPoint slide
Synthesis of Combretastatin A-4 and 3′-Aminocombretastatin A-4 derivatives with Aminoacid Containing Pendants and Study of their Interaction with Tubulin and as Downregulators of the VEGF, hTERT and c-Myc Gene Expression
Natural product combretastatin A-4 (CA-4) and its nitrogenated analogue 3&prime
Stereoselective 1,3-Dipolar Cycloadditions of a Chiral Nitrone Derived from Erythrulose. An Experimental and DFT Theoretical Study
We have investigated several 1,3-dipolar cycloadditions of a chiral nitrone prepared from L-erythrulose. While cycloadditions to carbon-carbon multiple bonds of dipolarophiles such as ethyl acrylate, ethyl propiolate, or dimethyl acetylenedicarboxylate were poorly stereoselective, reaction with acrylonitrile provided predominantly one diastereomeric adduct. Furthermore, the regioselectivity exhibited by the two structurally similar dipolarophiles ethyl acrylate and ethyl propiolate was found to be opposite. The molecular mechanisms of these cycloadditions have thus been investigated by means of density functional theory (DFT) methods with the B3LYP functional and the 6-31G and 6-31+G basis …
Chlorodicyclohexylborane-mediated aldol additions of alpha,alpha'-dioxygenated ketones.
Boron aldol additions of variously O-protected alpha,alpha'-dioxygenated ketones using dicyclohexylboron chloride and a tertiary amine have been investigated. The stereoselectivity of the process was dependent on the protecting group on the alpha-oxygen atoms. Notably, ketones with bulky silyloxy groups gave syn aldols, most likely via Z enolates. This rules out the participation of chelates during the enolization process, at least in the presence of such sterically crowded protecting groups. An alternative explanation is offered.
Synthesis of Protected Enantiopure Erythrulose Derivatives
D- and l-Erythrulose derivatives 2–6 bearing protective O-silyl and O-benzyl groups in various positions were synthesized in enantiopure form from l-ascorbic acid, D-isoascorbic acid, and D-glucose.
Diastereoselectivity in Organometallic Additions to the Carbonyl Group of Protected Erythrulose Derivatives
We have investigated a number of nucleophillic additions to L-erythrulose derivatives (4-12) bearing protective O-silyl, O-benzyl, and O-trityl groups in various relative positions. The results are discussed in the frame of chelated vs nonchelated transition states with additional support of previously published theoretical calculations. Sound evidence appears to exist for the formation of alpha-chelates as the key intermediates in nucleophillic additions to these alpha,beta-dioxygenated ketones. Since such evidence is still lacking in the case of beta-chelates, proposals of their intermediacy have been relegated in favor of the more solid Felkin-Anh model, which predicts the same stereoche…
Synthesis of honokiol analogues and evaluation of their modulating action on VEGF protein secretion and telomerase-related gene expressions
A group of 36 biphenyl derivatives structurally related to honokiol were synthesized by means of Suzuki coupling reactions. Their cytotoxicities were evaluated and compared to that of honokiol. Some of the compounds were then evaluated for their ability to downregulate the secretion of the VEGF protein and the expression of the VEGF, hTERT, and c-Myc genes; the two latter involved in the activation of telomerase in tumoral cells. Some of the synthetized derivatives showed promising pharmacological features as they exhibited IC50 values in low micromolar range, good therapeutic margins, and a multiple mode of action on tumor cells based on the inhibition of VEGF and, at the same time, of the…
Design and synthesis of pironetin analogue/colchicine hybrids and study of their cytotoxic activity and mechanisms of interaction with tubulin
We here report the synthesis of a series of 12 hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment. The two fragments are connected through an ester-amide spacer of variable length. The cytotoxic activities of these compounds and their interactions with tubulin have been investigated. Relations between the structure and activity are discussed. Since the spacer is not long enough to permit a simultaneous binding of the hybrid molecules to the colchicine and pironetin sites on tubulin, a further feature investigated was whether these molecules would interact with the latter through the pironetin end (irreversible covalent binding) or through the colchicine end (…
Synthesis of N-acyl Derivatives of Aminocombretastatin A-4 and Study of their Interaction with Tubulin and Downregulation of c-Myc.
11 p.-9 fig.-4 tab.