Anna Albrecht

Organocatalytic asymmetric synthesis of organophosphorus compounds.

240 Years have passed since the discovery of elemental phosphorus. During that time organophosphorus chemistry has emerged as an interesting and exciting field of research. Recently organophosphorus chemistry has been raised to a new level. Organophosphorus compounds have found applications in asymmetric organocatalysis for the synthesis of optically active compounds of synthetic or biological importance. The aim of this review article is to present recent contributions to this developing field of chemistry and to point out synthetic advantages of methodologies developed so far.

Enantioselective H‐Bond‐Directing Approach for Trienamine‐mediated Reactions in Asymmetric Synthesis

Right direction: The presented enantioselective strategy for the preparation of diversely functionalized tetrahydroxanthones is based on a trienamine-mediated cycloaddition between 2,4-dieneals and activated chromones. It is possibile to control the stereochemical outcome of such reactions by employing an H-bond-directing aminocatalyst.

Asymmetric organocatalytic [3 + 2]-annulation strategy for the synthesis of N-fused heteroaromatic compounds

Hydroxyalkyl- or aminoalkyl-substituted N-fused heteroaromatic compounds can be efficiently accessed via an organocatalytic [3 + 2]-annulation strategy. The developed cascades proceed in a highly enantioselective manner and benefit from broad substrate scope, operational simplicity, easily available starting materials as well as low catalyst loadings.

Synthesis and biological evaluation of α-methylidene-δ-lactones with 3,4-dihydrocoumarin skeleton

A series of new 3-methylidenechroman-2-ones bearing various aromatic moieties and various substituents at position 4 were synthesized in a three step reaction sequence. Friedel-Crafts alkylation of phenols or naphthols using ethyl 3-methoxy-2-diethoxyphosphorylacrylate in the presence of trifluoromethanesulphonic acid gave 3-diethoxyphosphorylchromen-2-ones. These compounds were employed as Michael acceptors in the reaction with Grignard reagents to give adducts which were finally used as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. All obtained 3-methylidenechroman-2-ones were tested against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer and HT-29 colon cancer adenocarcinomas. Several obtained methylidenechromanones displayed high cytotoxic activity with IC(50) values below 1 μM, mainly against leukemia and MCF-7 cell lines. Investigation of structure-activity relationships revealed that the presence of additional, ortho-fused benzene ring and n-butyl or i-propyl group in position 4 enhances the activity. Selected methylidenechromanones were also tested on normal human umbilical vein endothelial cells (HUVEC) and chromanone 14o was found to be eightfold more toxic against MCF-7 than normal cells. Furthermore, antimicrobial assays revealed that chromanone 14n is highly active and bactericidal at concentration equal to MIC or 2MIC against nosocomial and community-associated staphylococci (MRSA) which are resistant to most or all available therapeutic classes of antimicrobial drugs.

A convenient synthesis and cytotoxic evaluation of β-aryl-α-methylidene-γ-lactones and β-aryl-α-methylidene-γ-lactams

3-Aryl-2-diethoxyphosphoryl-4-nitrohexanoates 8, obtained by Michael addition of ethyl diethoxyphosphorylacetate 6 to 1-aryl-2-nitro-1-butenes 7, were utilized as convenient common intermediates in the synthesis of β-aryl-γ-ethyl-α-methylidene-γ-lactones 17 and β-aryl-γ-ethyl-α-methylidene-γ-lactams 21. Transformation of the nitro functionality in 8 into a hydroxyl or amino group and cyclization yielded lactones 16 or lactams 19, which were used in Horner–Wadsworth–Emmons olefination of formaldehyde to give target compounds in good yields. Cytotoxicity of these compounds was evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines, HL-60 and NALM-6. Two of the obtained compounds 17b,c with 4-bromophenyl and 4-methylphenyl substituents in the β position proved to be very potent against all three cell lines with IC50 values lower than 6 μM.

Organocatalytic strategies for the construction of optically active imidazoles, oxazoles, and thiazoles.

This study demonstrates the first enantioselective synthesis of hydroxyalkyl- and aminoalkyl-substituted imidazoles, oxazoles, and thiazoles. The approach developed utilizes a highly effective one-pot reaction cascade that consists of either an organocatalytic epoxidation or aziridination of α,β-unsaturated aldehydes coupled with a [3+2]-annulation, in which amidines, ureas, or thioureas act as effective 1,3-dinucleophilic species. The methodology described benefits from low catalyst loadings, commercially and readily available starting materials, and mild reaction conditions.

Asymmetric Synthesis of Hexahydropyrrolo-isoquinolines by an Organocatalytic Three-Component Reaction

The pyrrolo-isoquinoline moiety is present in alkaloid families such as erythrines, lamellarins, and pyrrolo ACHTUNGTRENNUNG[2,1a]isoquinoline derivatives, all of which exhibit biological activities. The importance of this heterocyclic system is further enhanced by its utility as an intermediate for the synthesis of alkaloids. Consequently, the interest in new synthetic methodologies for this moiety has increased. Three strategies have been developed for the asymmetric construction of polyhydropyrrolo ACHTUNGTRENNUNG[2,1-a]isoquinoline derivatives: a) N-acyliminium cyclization, b) Mitsunobu reaction of optically pure 3-(tetrahydroisoquinolin-1-yl)propan-1-oles, and c) asymmetric hydrogenation of prochiral iminium salts with a chiral metal complex. 9] A diastereoselective route to this moiety involving a [3+2]-cycloaddition of 3,4-dihydroisoquinolinium ylides to chiral dipolarophiles was recently presented. One strategy to optically active polysubstituted pyrrolidines is the metalor organocatalyzed [3+2]-cycloaddition of alkenes with azomethines. However, these reactions focus on a-iminoesters as azomethine ylide precursors and only recently has an organocatalytic [3+2]-cycloaddition of azomethine ylides to a,b-unsaturated aldehydes been presented. Herein we present a new multicomponent concept for the construction of hexahydropyrrolo ACHTUNGTRENNUNG[2,1-a]isoquinoline derivatives. The concept is based on a [3+2]-cycloaddition reaction of in situ generated dihydroisoquinolinium ylides, from the corresponding imines and a-bromoesters or ketone, to a,b-unsaturated aldehydes, and is catalyzed by a chiral pyrrolidine in the presence of a base (Scheme 1). This multicomponent approach allows the formation of two new C C bonds, a C N bond, and four stereocenters in one-step. The three-component reaction between 6,7-dimethoxy3,4-dihydroisoquinoline HCl (1 a), methyl 2-bromopropanoate (2 a), and cinnamic aldehyde (3 a) was the model system for optimization of the experimental parameters. (S)-2-(Diphenyl(trimethylsilyloxy)methyl)pyrrolidine (4 a), Na2CO3, CH2Cl2, and room temperature were the best conditions for the [3+2]-cycloaddition and gave the optically active product, as the conjugated ester 5 a, in high yields, good diastereoselectivity and an excellent enantioselectivity of 95 % ee. The scope of the three-component [3+2]-cycloaddition using different a,b-unsaturated aldehydes is given in Table 1.

Organophosphorus reagents in organocatalysis: synthesis of optically active α-methylene-δ-lactones and δ-lactams.

In this paper we describe new asymmetric, catalytic strategies for the synthesis of biologically important α-methylene-δ-lactones and δ-lactams. The elaborated protocols utilize iminium-ion-mediated Michael addition of trimethyl phosphonoacetate to α,β-unsaturated aldehydes catalyzed by (S)-(-)-α,α-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether as the key step. Enantiomerically enriched Michael adducts are employed in three different reaction pathways. Transformation into α-methylene-δ-lactones is realized by a sequence of reactions involving chemoselective reduction of the aldehyde, followed by a trifluoroacetic acid (TFA)-mediated cyclization and Horner-Wadsworth-Emmons olefination of formaldehyde. On the other hand, indolo[2,3-a]quinolizine-framework-containing products can be accessed when enantiomerically enriched Michael adducts are employed in a Pictet-Spengler reaction with tryptamine, followed by Horner-Wadsworth-Emmons olefination. Finally, reductive amination of the Michael adducts by using methylamine and Horner-Wadsworth-Emmons olefination of formaldehyde is demonstrated to give α-methylene-δ-lactams. The developed strategies can be realized without the purification of intermediates, thus greatly increasing their practicality.