Highly functionalised organolithium and organoboron reagents for the preparation of enantiomerically pure α-amino acids

Homochiral, highly functionalised organolithium reagents derived from l-serine have been generated and reacted with electrophiles. The novel enantiomerically pure adducts thus obtained were then converted, through β-amino alcohols, into novel non-proteinogenic α-amino acids. The methodology also made available a novel boronic acid which was then employed as a Suzuki cross-coupling partner, elaborating a new pathway to phenylalanine analogues.     

Synthesis of both enantiomers of methylenolactocin,nephrosterinic acid and protolichesterinic acid via tandem aldol–lactonization reactions

Both forms of the enantiomerically pure methylenolactocin, nephrosterinic and protolichesterinic acid have been synthesized via tandem aldol–lactonization reactions from corresponding optically active itaconate–anthracene adducts.     

Diastereoselective Michael addition of (S)-mandelic acid enolate to 2-arylidene-1,3-diketones: enantioselective diversity-oriented synthesis of densely substituted pyrazoles

A diversity-oriented approach to enantiomerically pure densely substituted pyrazoles, α-aryl-α-pyrazolylatrolactic acid and α-aryl-α-pyrazolylacetophenones has been developed. The approach utilises the conjugated addition of the lithium enolate of the (2S,5S)-cis-1,3-dioxolan-4-one derived from optically active (S)-mandelic acid and pivalaldehyde to several 2-arylidene-1,3-diketones, which proceeds readily to give the corresponding Michael adducts in good yields and diastereoselectivities. The cyclocondensation of the 1,3-diketone moieties present in Michael adducts with several hydrazines leads to enantiomerically pure densely substituted pyrazoles. Subsequent basic hydrolysis of the dioxolanone moiety present in these products leads to enantiomerically pure α-aryl-α-pyrazolylatrolactic acids. Finally, oxidative decarboxylation of these using oxygen, pivalaldehyde and the Co(III)-Me₂opba complex as catalyst gives α-aryl-α-pyrazolylacetophenones. In this approach four points of diversity are introduced, one of them is the configuration of the (S)-mandelic acid, which acts as an umpoled chiral equivalent of the benzoyl anion.     

2H-Azirine 3-phosphonates: a new class of chiral iminodienophiles. Asymmetric synthesis of quaternary piperidine phosphonates

[reaction: see text] Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphonates and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts that on hydrogenation afford the first examples of enantiopure quaternary piperidine phosphonates.     

Regioselective carbon-carbon bond cleavage in the oxidation of cyclopropenylcarbinols

The strained double bond of cyclopropenylcarbinols undergoes a facile oxidation reaction to lead to unsaturated carbonyl derivatives. The distribution of the formed products depends on the relative stability of carbon-centered radical species, and the Sharpless kinetic resolution leads to enantiomerically pure Baylis-Hillman enal adducts.     

Stereoselective preparation of β,γ-methano-GABA derivatives

The Kulinkovich-de Meijere reaction between an unsaturated Grignard reagent and a chiral amide takes place with a high trans stereoselectivity and provides a convenient access to non-racemic trans cyclopropylamines. These compounds are transformed in four steps into the corresponding N-protected β,γ-methano-GABA derivatives, which are obtained for the first time in enantiomerically pure form. The corresponding transformations of the cis cyclopropylamine adducts are also described.     

Stereodivergent approaches to the synthesis of isoxazolidine analogues of alpha-amino acid nucleosides. Total synthesis of isoxazolidinyl deoxypolyoxin C and uracil polyoxin C

The synthesis of new nucleoside analogues is currently of high interest. We report here full details of a study leading to the synthesis of novel isoxazolidinyl analogues of alpha-amino acid nucleosides. Three different synthetic approaches starting from L-serine have been evaluated for the construction of the isoxazolidine ring. These approaches consisted of Michael addition of N-benzylhydroxylamine to alpha,beta-unsaturated esters, nucleophilic addition of silyl ketene acetals to nitrones and 1, 3-dipolar cycloaddition of nitrones with vinyl acetate. Both Michael addition and nucleophilic addition of enolates could be carried out with stereocontrol at the newly formed stereogenic carbon. The stereocontrol observed in these reactions arises from the protecting group arrangement in the L-serine-derived substrates. Thus, whereas compounds having a diprotected nitrogen led to syn adducts, compounds having a monoprotected nitrogen gave rise to anti adducts. On the other hand, substrates having either a diprotected or monoprotected nitrogen atom led to anti adducts through the cycloaddition route. So, by choosing the appropriate route, isoxazolidinyl analogues having either syn or anti configuration with respect to the glycine unit can be prepared in enantiomerically pure form. The stereoselective synthesis of isoxazolidinyl analogues of deoxypolyoxin C and uracil polyoxin C in both D and L enantiomeric forms using these techniques has been achieved in good yields.     

Total syntheses of (-) epilupinine and (-)-tashiromine using imino-aldol reactions

Short routes to enantiomerically pure indolizidine and quinolizidine alkaloids have been developed using imino-aldol reactions of enolates derived from phenyl 5-chlorovalerate. High levels of syn selectivity (dr ～13-16:1) were obtained using lithium enolates of phenyl esters in combination with tert-butylsulfinyl imines. The imino-aldol adducts were deprotected and cyclized to afford (-)-epilupinine ((-)-2) and (-)-tashiromine ((-)-1) in two further steps.     

Asymmetric synthesis of chiral spiro bis(isoxazoline) and spiro (isoxazole–isoxazoline) ligands

Asymmetric synthesis of novel chiral ligands, bis(isoxazoline) on a spiro[4.4]nonane scaffold and isoxazole–isoxazoline on a spiro[4.5]decane scaffold, has been achieved by utilizing an enantiomerically pure alcohol as the starting material.     

Asymmetric Michael addition of formaldehyde N,N-dialkylhydrazones to alkylidene malonates

Enantiopure formaldehyde N,N-dialkylhydrazones 1 smoothly react with prochiral alkylidene malonates 2 in the presence of MgI2 to afford the corresponding Michael adducts 3 in excellent yields and good diastereoselectivities; direct racemization-free BF3.OEt2-catalyzed thiolysis of the hydrazone C=N bond affords the corresponding dithioketals 7 in optically pure or enantiomerically enriched form.     

Chiral high-performance liquid chromatography analysis of alpha-amino acid mixtures using a novel SH reagent--N-R-mandelyl-L-cysteine and traditional enantiomeric thiols for precolumn derivatization

Several chiral thiols, i.e. traditionally used enantiomerically pure SH reagents and novel N-R-mandelyl-L-cysteine (R-NMC) containing additional chiral center, have been applied as co-reagents in precolumn derivatization with o-phthalaldehyde for enantiomeric HPLC analysis of individual alpha-amino acids and their mixtures. The R-NMC-derived isoindoles as well as adducts with other thiols have a characteristic absorption maximum at 340 nm, and are highly fluorescent allowing detection of 10 microg/l of an amino acid. Investigated 19 amino acids were analyzed separately and in a mixture by a gradient HPLC after precolumn derivatization. The chromatographic behavior of formed isoindoles substantially differs for each of the thiols used for modification. In contrast to traditional enantiomeric thiols application of diastereomeric R-NMC provides higher resolution for alpha-amino acid enantiomers, with L,D-elution order (except for Arg). Combined use of R-NMC and other thiol enlarges the possibilities of this method, allowing accurate chiral analysis of complex amino acid mixtures.     

Sulfinyl-directed diastereoselective

Introduction of a homochiral p-tolylsulfinyl group at an appropriate position in the alkene accelerates the thermal [5C + 2C] intramolecular cycloaddition to beta-silyloxy-gamma-pyrones and, most importantly, leads to excellent levels of diastereodifferentiation. The resulting adducts can be easily desulfinylated to give optically active 8-oxabicyclic[3.2.1]octane intermediates which by virtue of their rich functionalization might be susceptible to elaboration into enantiomerically pure natural products containing seven-membered carbocycles and tetrahydrofurans.     

Synthesis of Novel Chiral Diol Ligands for the Enantioselective Reactions

The chiral diols ((,(,((,((-Tetraaryl-1,3-dioxolane-4,5-dimethanols) have been used for the formation of cyclic titanates and similar derivatives of Mg, Al and Zr. These complexes of oxophilic metal centers were employed in catalytic and stiochiometric enantioselective reactions such as enantioselective addition reactions of carbon-centered nucleophiles to aldehydes1, [2+2] cycloadditions2, and Diels-Alder reactions3. So far, the two hydrogen atoms of all this type of diols are in trans form…     

Tandem enantioselective organo- and biocatalysis: a direct entry for the synthesis of enantiomerically pure aldols

Direct proline-catalyzed aldol reactions were linked in sequence with lipase-catalyzed kinetic resolutions to afford enantiomerically pure (>99% ee) aldol adducts in higher conversion than a standard resolution of racemic materials. The combination of organocatalytic aldol reactions and enzymatic kinetic resolutions provided exclusively either the (R)- or (S)-enantiomer of the aldol adducts even though an (R)-selective lipase catalyzed the kinetic resolutions. Furthermore, the one-pot tandem reactions are inexpensive, are operationally simple, circumvents the use of organic solvent and are environmentally benign.     

Development of chiral stabilised azomethine ylids: A chiral memory relay system.

Chiral, stabilised azomethine ylids incorporated in cyclic templates derived from (R)- or (S)-2-phenylglycinol and (S)-valine undergo enantioselective 1,3-dipolar cycloaddition reactions with a variety of dipolarophiles. Removal of the template in the case of adducts derived originally from (S)-valine furnishes enantiomerically pure -substituted proline derivatives.     

Synthesis of L-4,4-difluoroglutamic acid via nucleophilic addition to a chiral aldehyde

Fluorine-containing derivatives of amino acids are assuming increasing importance as probes of biological function and enzyme mechanism. We now report a new, flexible route to enantiomerically pure L-4,4-difluoroglutamic acid that exploits the addition of difluorinated nucleophiles to configurationally stable alpha-aminoaldehydes. Conversion of the difluorinated adducts to L-4,4-difluoroglutamic acid can be accomplished in three steps by Barton-McCombie dehydroxylation and acid hydrolysis.     

Crystallisation-induced asymmetric transformation (CIAT) for the synthesis of dipeptides containing homophenylalanine

A novel synthesis of highly enantioenriched dipeptides containing homophenylalanine is described. The process involves a crystallisation-induced asymmetric transformation (CIAT) in a Michael addition followed by exhaustive reduction. A unique example of a formally stereodivergent CIAT in conjugate addition of an achiral N-nucleophile to enantiomerically pure Michael acceptor has been discovered.     

Highly enantioselective Henry reaction catalyzed by chiral tridentate heteroorganic ligands

New tridentate enantiomerically pure heteroatom catalysts, containing hydroxyl, sulfinyl and amino groups, proved to be highly efficient in the enantioselective nitroaldol (Henry) reaction to give the desired adducts in very high yields (up to 90%) and with ees up to 98%. The influence of the stereogenic centres located on the sulfinyl sulfur atom and in the amine moiety is also discussed.     

Stereoselective synthesis of the 1,N-deoxyguanosine adducts of cinnamaldehyde. A stereocontrolled route to deoxyguanosine adducts of α,β-unsaturated aldehydes

α,β-Unsaturated aldehydes (enals) react with deoxyguanosine and have mutagenic potential. For higher enals, the reaction of deoxyguanosine gives diastereomeric 6-substituted 8-hydroxypyrimidopurinone products. These stereoisomers may have different local conformations in DNA, which may have biological consequences. We have developed a stereospecific synthesis of 1,N²-deoxyguanosine adducts of cinnamaldehyde. The key step is the synthesis is a metal-promoted intramolecular C-H insertion reaction of nitrogen of an enantiomerically pure sulfamate ester. The approach may be general for the stereocontrolled synthesis of this class of DNA adducts and can be applied to the preparation of site-specifically adducted oligonucleotides.     

A novel asymmetric approach to a densely functionalized lactarane ring system through a domino ring opening-ring closing metathesis of a norbornene derivative

A novel route for the synthesis of a highly functionalized lactarane skeleton in enantiomerically pure form is described via ROM-RCM of an appropriately constructed norbornene derivative as the key step.