The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate.

The synthesis of seven pyrano[3,2-a]carbazole alkaloids has been achieved using their putative biogenetic precursor 2-hydroxy-6-methylcarbazole as key intermediate.

The thesis titled “Stereoselective synthesis of bio-active styryllactones” comprises an introduction about styryllactones and three sections delineating the results and discussion about the synthesis of styryllactones and experimental section. Trees of the genus Goniothalamus of the plant family Annonaceae in South East Asia has been known for a long time for their proven use in folk medicine. The research group of McLaughlin isolated and characterized a series of styryllactones, possessing significant to marginal cytotoxic activity against human tumor cell lines. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis. Classification of these styryllactones is based on the structural characteristics of the six different skeletons as shown in Figure 1. It was proposed by Shing et al. that the bio-synthesis of styryllactones 1-7 occur via the shikimic acid pathway. This proceeds through the formation of cinnamic acid from phenylalanine, followed by the incorporation of two acetate–malonate units activated as co-enzyme A, generating the styryl-pyrone, goniothalamin 9 a key styryllactone, which on further hydroxylation/oxidation leads to the formation of other styryllactones Section 1: Stereoselective synthesis of styryllactones containing furanofurone, pyrano-pyrone and styryl-pyrone structural units. In this section of the thesis, stereoselective total synthesis of furano-furone, pyrano-pyrone and styryl-pyrone type styryllactones (+)-7-epi-goniofufurone 1, (+)-goniofufurone 2, (+)goniopypyrone 3, (+)-goniotriol 4, (+)-9-deoxygoniopypyrone 5 and (+)-goniodiol 6 is discussed. It is anticipated that the masked tetrol 13, comprising an alkene tether and four contiguous hydroxy groups installed with definite configuration would serve as the intermediate for the synthesis of styryllactones 1-6. It is relied on exploiting the hydroxy directed lactonization via the oxidation of alkene in 13, and subsequent elaboration to styryllactones 1-6. Bis-dimethylamide 10, derived from D-(−)-tartaric acid was identified as the suitable precursor for the synthesis of 13. Synthesis of masked tetrol 13 is accomplished from 10 involving a combination of selective Grignard additions and a stereoselective reduction (Scheme 2). Section 2: Stereoselective synthesis of styryllactones containing tetrahydrofuran and furano-pyrone structural units This section deals with stereoselective synthesis of natural antitumor tetrahydrofuran containing natural product (+)-goniothalesdiol 8. Key features of the synthesis include a FeCl3 mediated formation of THF 15 with very high selectivity (Scheme 3). THF 15 is further elaborated into the furano-pyrone type styryllactones (+)-altholactone 7 and (−)-etharvensin 16 in good yields (Scheme 3). Section 3: Stereoselective total synthesis of (+)-cardiobutanolide Recently, a new styryllactone cardiobutanolide 20 was isolated from the stem bark of Goniothalamus cardiopetalus, together with four known styryllactones by Hisham et al. Stereoselective total synthesis of this natural product from D-(−)-tartaric acid is described in this section. Key features of the synthesis include the elaboration of the γ-hydroxy butyramide 17 obtained from the bis-dimethylamide 10, involving a combination of the addition of 1,3-dithian-2-yllithium and stereoselective reduction (Scheme 4). (For structural formula pl see the pdf file)

Les hétérocycles oxygénés, azotés et soufrés sont des motifs présents dans de nombreux produits naturels possédant des activités biologiques intéressantes. Plusieurs publications décrivant la synthèse de ces hétérocycles en particulier oxygénés et azotés reposent sur l’utilisation des métaux de transition en tant que catalyseur.Dans notre cas, nous nous sommes intéressés dans un premier temps à la synthèse cupro-catalysée des pyrano[3’,4’:4,5]imidazo[1,2-a]pyridin-1-ones selon une réaction tandem impliquant un couplage et une hétérocyclisation, à partir des dérivés de l’acide 3-iodo-, 3,6- ou (3,8) diiodoimidazo[1,2-a]pyridine-2-carboxylique et d’alcynes vrais en présence de sels de cuivre (I) dans le DMF. Les réactions développées ne nécessitent aucune utilisation de métaux de transition plus coûteux comme les complexes au palladium par exemple. / Heterocycles of oxygen, nitrogen and sulfur are patterns found in many natural products possessing interesting biological activities. Several researchers describe the synthesis of oxygen and nitrogen based heterocycles using transition metals as catalyst.In the present study, we focused initially on the copper-catalyzed synthesis of pyrano[3',4':4,5]imidazo[1,2-a]pyridin-1-ones by a tandem coupling-heterocyclisation reaction from derivatives of 3-iodo-, 3,6- or (3,8) diiodoimidazo[1,2-a]pyridine-2-carboxylic acid and terminal alkynes in the presence of copper (I) salts as catalyst in DMF. This procedure does not require the use of any expensive transition metal complexes like palladium and supplement any additives. The extension of this methodology to 2,3,5-triiodobenzoic acid allowed the regioselective synthesis of new isocoumarins substituted in positions 3, 5 and 7. Regioselective reactivity of iodine atoms in position 5 and 7 has been studied by palladium coupling reactions and nucleophilic substitution to broad its synthesis to a wide variety of new substituted isocoumarins.

The thesis entitled ‘Studies of NIS Mediated Cyclopropane Ring Opening Reactions in Carbohydrate Chemistry’ is divided into four chapters. Chapter 1: Section 1: Efficient Synthesis of Fused Perhydrofuro[2,3-b]pyrans (and furans) by Ring Opening of 1,2-Cyclopropanated Sugar Derivatives. In this section a general and efficient methodology for the synthesis of carbohydrate derived perhydrofuro[2,3-b]pyrans (and furans) from the corresponding 1,2-cyclopropane carboxylates has been discussed. A wide range of linear-fused perhydrofuro[2,3-b]pyran or furan ring systems are encountered in a number of biologically active natural products. A few approaches are available for the construction of this kind of fused motifs which involve harsh reaction conditions and lengthy reaction sequence. The methodology utilizes the potential ability of cyclopropanated sugars to undergo N-iodosuccinimide (NIS) mediated electrophilic ring opening assisted by the pyran ring oxygen followed by intramolecular trapping of oxonium intermediate to generate the furan ring system. Cyclopropantion of tribenzyl glucal using methyl diazoacetate and catalytic amount of dirhodiumtetracetate furnished corresponding exo-1,2-cyclopropane carboxylate exclusively. To generate a nucleophile, cyclopropane carboxylate ester was reduced to the corresponding alcohol which upon treatment with NIS in CH3CN underwent ring opening followed by intramolecular ring closure to give the corresponding perhydro[2,3-b]furopyran along with an oxidized product. After various modifications we found that using CH2Cl2 as a solvent gave the expected perhydrofuropyran as the sole product in good yield (Scheme I). The stereochemistry of the product was established on the basis of 1H-1H NOESY experiment. There are many natural products that contain the perhydrofuro[2,3-b]furyl glycal core such as clerodin, jodrelline B and caryoptin, which show insect anti-feedant properties. With this in mind, the methodology has been successfully extended to the cyclopropanated tetrahydrofuran derivatives resulting in the synthesis of furofuryl glycal moiety (Scheme II). Scheme II Chapter 1: Section 2: Synthesis of Carbohydrate Derived Fused Perhydrofuro/pyrano[2,3-b]-γ-butyrolactones. In this section a general and efficient methodology for the synthesis of carbohydrate derived perhydrofuro/pyrano[2,3-b]-γ-butyrolactones has been discussed. The fusion of the γ-butyrolactone onto a substituted tetrahydrofuran/pyran ring makes a distinctive class natural diterpenoids. Representative members of this family include the marine diterpenoids norrisilide and miniolutelide A. In this chapter we describe a neutral and general method for the construction of perhydrofuro/pyrano[2,3-b]-γ-butyrolactones by NIS mediated ring opening of carbohydrate derived 1,2-cyclopropane carboxylic acids (Scheme III). Scheme III The present strategy is complementary to the existing methods and it is useful since it incorporates an additional chiral center in the molecule under milder conditions, which can be used for further transformations. Chapter 2: Ring Opening of Activated Cyclopropanes with NIS/NaN3: One-pot Synthesis of C-1 Linked Pseudo Disaccharides. Ring opening reactions of activated cyclopropanes have been widely used in organic synthesis. But they are restricted to only selected nucleophiles such as alcohol/ water, as most of the ring opening reactions need acidic activation. This chapter deals with studies of reactivity of various activated cyclopropanes with NIS as a neutral activator and sodium azide as a source of nitrogen nucleophile (Scheme IV). Scheme IV We have clearly demonstrated not only the importance of the donor-acceptor feature in the cyclopropanes in the electrophilic ring opening reaction, but also the selectivity in its functionality. Scheme V This methodology has been successfully utilized in a one-pot synthesis of C-1 linked pseudo-disaccharides from carbohydrate derived 1,2-cyclopropane carboxylates (Scheme V). Chapter 3: Synthesis of Unnatural C-2 Amino Acid Nucleosides Using NIS Mediated Ring Opening of 1,2-Cyclopropane Carboxylated Sugar Derivatives. In this chapter, we have efficiently demonstrated the utility of NIS mediated regioselective ring opening of carbohydrate derived donor-acceptor cyclopropanes for the synthesis of C-2 amino acid nucleosides. This leads to a new class of analogs of peptidyl nucleosides (Scheme VI). Scheme VI One of the advantageous factors is the attachment of nucleobase as well as generation of amino acid precursor in the same reaction which avoids lengthy reaction sequence. We have also shown the synthetic utility of our methodology to pyrimidine based furanosyl C-2 amino acid nucleosides which are of interest, since polyoxins having similar structural core exhibit antifungal activity (Scheme VII). Chapter 4: Attempts Towards the Synthesis of Carbohydrate Derived Spiro-perhydrofuropyrans Using NIS Mediated Cyclopropane Ring Opening Reaction. In this chapter we present various attempts to synthesize spiro-perhydrofuropyran/furans by ring opening of spiro-cylopropane derivatives and attempts towards stereoselective synthesis of spiro-cyclopropane carboxylates. Spiroacetal can be synthesized from the corresponding exo-cyclopropyl methanol, which can be obtained from the corresponding exo- cyclopropane carboxylate. The cyclopropyl carboxylate can be obtained from an exo- vinyl ether. Cyclopropanation of carbohydrate derived exo-glycal failed to give any selectivity under a variety of reaction conditions (Scheme VIII). Carbohydrate derived C1-unsaturated ester on cyclopropanation reaction using standard conditions (Pd(OAc)2/CH2N2) was found to be inert. The reaction under Simmons-Smith cyclopropanation conditions also gave similar results. Reduction of the ester part of the molecule to the corresponding alcohol was found to be helpful in the Simmon-Smith cyclopropanation reaction (CH2I2, Et2Zn) to obtain the corresponding exo-cyclopropane, but disappointingly without any selectivity (Scheme IX). In order to get exo-cyclopropane carboxylate with high stereoselectivity, we decided to use one of the hydroxyl group present in the molecule, as a chiral auxiliary. All the established methods for the diazoester formation failed to attach diazo ester at C-4 position (Scheme X). Scheme X (For structural formula pl see the pdf file)