Anthracyclines and related substances. 4. A novel regio- and stereoselective total synthesis of 7-epidaunomycinone and daunomycinone.

Daunomycinone $\text{2a}$ has been synthesized by a novel regio- and stereoselective route that establishes the tetracyclic framework and the C-7 oxygen in naphthacenol $\text{5c}$ via a double Friedel-Crafts acylation.     

Studies on the synthesis of akuammiline-type alkaloids. Construction of the hexahydro-1,5-methanoazocino[3,4-b)indole fragment

A three step route to the title tetracyclic substructure of akuammiline-type alkaloids consisting in the nucleophilic addition of an ester α-anion to an N-alkylpyridinium salt, acid-induced cyclization of the resultant 1,4-dihydropyridine, and stereoselective elaboration of the ethylidene substituent is reported.     

Electrochemical studies of biologically active indolizines

The electrochemical behavior of indolizine ethers, esters, tosylates, sulfonates and other indolizine and azaindolizine derivatives has been investigated by cyclic voltammetry and preparative electrolysis. The cyclic voltammetric data show that the E° values, taken as the midpoints between the anodic and cathodic peak potentials, are sensitive to the identities of the substituents at C-1, C-2 and C-7 positions. The E° values have been correlated with the Hammett substituent parameters. As expected, low E° values are seen for electron donating substituents and higher E° values are seen for electron withdrawing substituents. The cyclic voltammograms of indolizine derivatives with an oxygen atom connected to the C-1 position exhibit a one-electron reversible oxidation and a further, less well-defined, one-electron irreversible oxidation at higher E° values. The cyclic voltammograms of indolizines with hydrogen atom or thienyl substituents connected to the C-1 position exhibit only a one-electron irreversible oxidation. Electrochemical bulk oxidations of indolizines with an oxygen atom at the C-1 position afforded oxoindolizinium salts in decent yields, whereas indolizines with a hydrogen atom at C-1 afforded 1,1′ dimers of indolizines as products in good yields. Bulk oxidation of 1-(α-hydroxybenzyl)-2,3-diphenylindolizine-7-carbonitrile afforded an unexpected ketone product in which the carbonyl group of the indolizine is connected at C-8 instead of at the C-1 position of the starting material. The findings described herein support our hypothesis that certain indolizine derivatives may inhibit lipid peroxidation by an electron transfer mechanism.     

Synthesis and Modeling of Ezetimibe Analogues

Ezetimibe is a well-known drug that lowers blood cholesterol levels by reducing its absorption in the small intestine when joining to Niemann-Pick C1-like protein (NPC1L1). A ligand-based study on ezetimibe analogues is reported, together with one-hit synthesis, highlighted in the study. A convenient asymmetric synthesis of (2S,3S)-N-α-(R)-methylbenzyl-3-methoxycarbonylethyl-4-methoxyphenyl β-lactam is described starting from Baylis–Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland–Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent inversion of ester and acid functionality paves the way to the lactam core after monodebenzylation and lactam formation. It also shows interesting results when it comes to a pharmacophore study based on ezetimibe as the main ligand in lowering blood cholesterol levels, revealing which substituents on the azetidine-2-one ring are more similar to the ezetimibe skeleton and will more likely bind to NPC1L1 than ezetimibe.     

Synthese de la cyclo-5'-8 desoxy-5' adenosine: stereochimie et mecanisme de la cyclisation d'un derive de l'iodo-5' adenosine par le zinc

N,N'-Dibenzoyl 2', 3'-O-isopropylidene 5'-deoxy 5'-iodo adenosine can efficiently transformed into the corresponding 5',8-cyclo-7,8-dihydronucleoside by zinc in pyridine. Only one diastereoisomer is obtained. By spin decoupling and NOE techniques at 250 MHz, the R-configuration at C-8 was established. This compound showed typical dihedral angles of about 90° for the vicinal protons H-1', H-2' and H-3', H-4'. Using adenosine derivatives stereospecifically labelled at C-5', it was demonstrated that the cyclisation occurs with racemisation at that position.     

An enantioselective synthetic route to cis-2,4-disubstituted and 2,4-bridged piperidines

A synthetic route to enantiopure cis-2,4-disubstituted and 2,4-bridged piperidines is reported, the key step being a stereoselective conjugate addition of an organocuprate to a phenylglycinol-derived unsaturated lactam bearing a substituent at the 8a-position.     

Sequential ring-closing metathesis–vinyl halide Heck cyclization reactions: access to the tetracyclic ring system of ervitsine

A chemoselective indole-templated ring-closing metathesis is used to assemble the cyclohepta[b]indole substructure of the indole alkaloid ervitsine. A subsequent intramolecular Heck coupling of the resulting alkene functionality with an amino-tethered vinyl halide accomplishes the closure of the unique 2-azabicyclo[4.3.1]decane framework of the alkaloid with concomitant incorporation of the exocyclic E-ethylidene substituent.     

Synthesis of an external beta-turn based on the GLDV motif of cell adhesion proteins

The (3S,6S,10S)-7/5 bicyclic lactam 8, designed as an external turn constraint, was synthesised by a new stereoselective route involving Eschenmoser condensation. The cyclic peptide 35 containing the integrin recognition motif GLDV added across the amino and carboxyl groups of the lactam external constraint 8 was prepared.     

New chemo-enzymatic route toward N-acetylneuraminic acid derivatives with alkyl groups at C-7 hydroxyl group

Based on chemo-enzymatic regio- and stereoselective reactions, new routes toward C-4 substituted N-acetyl-d-mannosamine (ManNAc) and the corresponding sialic acids from d-glucal were established. Lipase-catalyzed regioselective transformation of d-glucal and related substrates furnished precursors on which carbamate and alkyl substituent were properly introduced at C-3 and at C-4, respectively. Cyclic carbamate formation through rhodium-nitrenoid intermediates with iodobenzene pivalate and tert-butyl alcohol proceeded in manno-configured at C-2 as well as α- at C-1, exclusively. Ring opening and deprotection under mild conditions furnished the target ManNAc derivatives, which were the substrates for aldolase-catalyzed reactions.     

Nucleophilic additions on acetyldioxanes derived from (−)-(1R)-myrtenal used as chiral auxiliaries: substituent effects on the stereochemical outcome

The synthesis of acetyldioxanes 4 and 9a starting from (?)-(1R)-myrtenal is described. The products were treated with a representative series of nucleophilic reagents (RMgX, RLi, NaBH₄ and LiAlH₄) to assess the effect of the substituent at C-3 on the stereochemical outcome. It was observed that the nucleophiles preferred the re-face of the CO group when the equatorial substituent at C-3 was a methyl group, whereas a phenyl group at the same position induced the addition through the si-face, thus allowing access to either desired stereochemistry of a final product. This behavior suggests that the formation of the expected Cram-chelated coordination complex takes a coplanar orientation with the C-3 equatorial substituent. Moreover, Grignard reagents were the most stereoselective nucleophiles. The stereochemistry of the addition was established by X-ray diffraction and chemical correlation.     

Stereoselective synthesis of rac-(8R,13S,14S)-7-oxa-estra-4,9-diene-3,17-dione

The first synthesis of a novel oxa-steroid, rac-(8R,13S,14S)-7-oxa-estra-4,9-diene-3,17-dione has been achieved via stereoselective catalytic hydrogenation of the tetra-substituted indene intermediate, whose structure was confirmed by X-ray crystallography. In contrast to the previous reports of similar indene systems, it was found that catalytic hydrogenation of indenes with a large substituent at the C-2 position and a bulky β-oriented protective group at the C-6 position resulted in cis-indanes instead of trans-indanes.     

A novel and efficient stereo-controlled synthesis of hexahydroquinolinones via the diene-transmissive hetero-Diels-Alder reaction of cross-conjugated azatrienes with ketenes and electrophilic dienophiles

The diene-transmissive hetero-Diels-Alder (DTHDA) reactions of cross-conjugated azatrienes (divinylimines or penta-1,4-dien-3-imines) having an N-aryl, N-alkyl, or N-dimethylamino substituent have been examined. The initial reaction of the azatrienes with diphenylketene at room temperature yielded β-lactams of [2+2] cycloadducts, which upon heating underwent [1,3]-sigmatropic rearrangement to produce the formal [4+2] cycloadducts. The reaction of N-phenylazatriene with dimethylketene or dichloroketene produced the [2+2] cycloadducts only, while the reaction of N-(dimethylamino)azatriene with dichloroketene gave the [4+2] cycloadduct without heating. When the [2+2] cycloadduct has two different vinyl substituents at C-4 of the β-lactam ring, the regioselectivity of the rearrangement depends on steric factors and the electronic demand of the substituents. The second Diels-Alder reaction of the initial [4+2] cycloadducts with electron-deficient dienophiles (TCNE, N-phenylmaleimide) stereoselectively yielded hexahydroquinolinone derivatives. Similarly, a tandem intermolecular-intramolecular mode of the aza-DTHDA reactions produced tetracyclic nitrogen-containing heterocycles in a regio- and stereoselective manner.     

Stereoselective synthesis of conformationally constrained (2S,3S)-3-hydroxyornithine

A convenient and efficient route is described for the highly stereoselective synthesis of δ-amino protected and conformationally restricted (2S,3S)-3-hydroxyornithine through the N-benzylnitrone adduct to the α,β-unsaturated bicyclic lactam 2 derived from (S)-pyroglutaminol.     

Stereoselective Introduction of Steroid Side Chains. Synthesis of Chenodeoxycholic Acid

A new short route to chenodeoxycholic acid has been developed. The synthesis is based on the stereoselective introduction of the steroidal side chain via an ene reaction of methyl acrylate and a (17Z)-ethylidene steroid prepared from androstenedione.     

Synthesis of an external β-turn based on the GLDV motif of cell adhesion proteins

The (3S,6S,10S)-7/5 bicyclic lactam 4, designed as an external turn constraint, was synthesised by a new stereoselective route involving Eschenmoser condensation. Calculated preferred conformations compare well with the preferred solid state conformation, obtained by X-ray crystallography. The lactam 4 was not a turn mimic in its own right but could be used as an external constraint to prepare the cyclic peptide 29 containing the integrin recognition motif GLDV. High-resolution NMR measurements were consistent with this compound having a single backbone conformation.     

Beiträge zur Chemie der Pyrrolpigmente, 11. Mitt.: Die Lichtabsorption geometrisch isomerer Arylmethyliden-pyrrolinone —Konformationsanalytische Studien

By investigation of the geometrical isomers of several substituted arylmethylidene-pyrrolinones using lanthanide induced shift experiments in connection with a computer program, the ring current model,PPP—SCF—LCAO—MO—CI calculations and UV spectroscopy the following conclusions could be drawn: The light absorptions ofZ- andE-isomers vary only in the case of different dihedral angles at the arylmethine bond. The dihedral angles in theE-isomers are determined by the substituent in 4-position of the lactam ring. Hydrogen makes no difference whereas methyl leads to a more twistedE-structure which therefore shows a marked hypsochromic shift of the intense long wavelength absorption band, as compared to the correspondingZ-isomer.     

Leucolusine, a tetracyclic alkaloid with a novel ring system incorporating an oxindole moiety and fused piperidine-tetrahydrofuran rings

A tetracyclic ring-opened oxindole alkaloid, possessing an unprecedented ring system incorporating fused piperidine-tetrahydrofuran rings, has been isolated from the Malayan species, Leuconotis griffithii. The structure was established by analysis of the spectroscopic data and a possible biogenetic pathway from an Aspidosperma precursor is presented.     

6-(Hetero)arylindolizino[1,2-c]quinolines as highly fluorescent chemical space: Synthesis and photophysical properties

A highly fluorescent indolizino[1,2-c]quinoline with a substituent at the C6 position was designed and synthesized as a new indolizine-quinoline hybrid structure via a tetracyclic lactam. Various (hetero)aryl groups were introduced at the C6 site of this basic skeleton to display intriguing photophysical properties.     

Stereoselective synthesis and Lewis acid mediated functionalization of novel 3-methylthio-β-lactams

A proficient etiquette for the stereoselective synthesis of novel 3-methylthio-β-lactams and their Lewis acid mediated functionalization is described. Treatment of 2-methylthioethanoic acid and appropriate imines in the Staudinger reaction leads to the stereocontrolled synthesis of novel trans-3-methylthio-β-lactams in excellent yields. cis-3-Chloro-3-methylthio-β-lactams, obtained from stereoselective chlorination of trans-3-methylthio-β-lactams using N-chlorosuccinimide (NCS) and AIBN, were subjected to Lewis acid (TiCl₄ or SnCl₄) mediated functionalization using various active aromatic, heterocyclic and aliphatic compounds (nucleophiles). This reaction provides an easy access to novel, stereoselective cis-3-monosubstituted-3-methylthio-β-lactams, which further undergo smooth desulfurization with Raney-nickel to afford C-3 cis- and trans-monosubstituted-β-lactams. The cis or trans configuration of the hydrogen/chloro/nucleophile substituent at C-3 was assigned with respect to C4–H.     

Synthetic studies on isoschizogamine: construction of [3.3.1] bicyclic aminal core by using oxidative skeletal rearrangement

The tetracyclic core structure of isoschizogamine containing aminal functionality was constructed by oxidative skeletal rearrangement of a 1,2-diaminoethene derivative. The 1,2-diaminoethane was prepared by palladium-catalyzed allylation at the 4a position of a 1,2,3,4-tetrahydro-β-carboline derivative and subsequent lactam formation. After the oxidative skeletal rearrangement using dimethyldioxirane, the allyl group was removed by a three-step sequence to provide the tetracyclic core skeleton of isoschizogamine with aminal functionality.