Summary of the Thesis

Transcription

1 CHAPTER V Summary of the Thesis The thesis concerns with the successful conversion of (2S,3S)- and (2S,3R)- tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids (Garcinia and Hibiscus acids) to 2S-Dialkyl 4-methoxy-5-oxo-2,5-dihydro-2,3-furandicarboxylates, analogues of the Quararibea metabolite chiral enolic γ-lactone (3-hydroxy-4,5- (R)-dimethyl-2(5H)-furanone). Chapter I provides the background and scope of the thesis. (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids, rarely exploited molecules isolated in large amounts from cheap natural sources, have been successfully used for the synthesis of several potential chiral entities like diols [trialkyl (1S,2S)- and (1S,2R)-1,2-dihydroxy1,2,3-propane tricarboxylates]; polyols [(4S,5S)-4-(2-Hydroxy-2,2-diarylethyl)-2,2-Dimethylα,α,α,α -tetraaryl-1,3-dioxalane-4,5-dimethanols]; pyrrolidinediones [Alkyl (2R)-[2(3S)-1-(4-methoxybenzyl)-3-hydroxy-2,5-dioxotetrahydro-1H-pyrrol-3-yl]- 2-hydroxyethanoate ] etc and analogues of natural products like mescaline isocitrimide lactone, (+) avenaciolide and (+) canadensolide. As the objective of the present study is to explore the possibility of using γ- butyrolactone based (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylic acids especially for the synthesis of chiral γ-butyrolactone based molecules, a systematic literature survey of biologically potent γ-butyrolactone based natural products has been presented in Chapter II of the thesis. The study reveals that several γ butyrolactone based molecules are available in the nature with matching structure and stereochemistry with that of (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids. Chiral γ-butyrolactone functionalized at the ring carbons play a key role in the

2 216 syntheses of many types of natural products serving as building blocks for alkaloids, macrocyclic antibiotics, lignan lactones, pheromones, antileukemics and flavor components. Owing to the importance of these class of compounds, in recent years, many optically active lactones have been the targets of an increasing number of synthetic efforts. A judicious conversion of the C2 and C3 carboxylic groups of the title compounds to desired functionality provides a number of biologically active natural products or useful intermediates for the synthesis of several natural products. Though known since the 1960s, synthetic efforts for the utilization of the title compounds as chirons are virtually absent. This is irrespective of the fact that these molecules can easily be made available from cheap natural sources. For the present study (2S,3S)- and (2S,3R) - tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids have been independently isolated from fresh plant sources and completely characterized. The optical integrity of the molecules has been established by a systematic VCD (Vibrational Circular Dichroism) analysis. The synthesis of analogues of the Quararibea metabolite chiral enolic-γlactone from (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3- furandicarboxylic acids have been included in Chapter III. Chiral enolic-γlactone (3-hydroxy-4,5-(R)-dimethyl-2(5H)-furanone) and few other related compounds isolated from a strongly odorous Mexican flowering plant; Quararibea funibris; are known to be responsible for the characteristic spicy odour which even persists for long in stored herbarium specimens. They are also used as a popular local folk medicine for cough, as antipyretic, to control menstrual disorders, psychopathic fears and as additives to chocolate drinks from pre-colombian times. The Zapotec people of Oaxaca, Mexico conducted funeral rites beneath the branches of the tree Quararibea funibris. However no reports are available for the enantiopure total synthesis of the above mentioned molecule.

3 217 Chiral butenolides form an important class of compounds which appear as substructures in many natural products and have been employed as key intermediates for the synthesis of a wide range of bioactive compounds with representation in over 13,000 natural products. The γ-butenolide synthon has become a valuable architectural platform for the development of new asymmetric methodologies. Often chiral butenolides were obtained either from carbohydrates, γ-keto acids, glutamic acid or from acyclic systems like acetylenic compounds, pyruvic acid derivatives, cyanohydrins of conjugated aldehydes etc, mostly involving multi step procedures or complex retro Diels-Alder strategies. Few naturally occurring molecules bearing butenolide moiety along with the existing strategies for their construction are being presented in chapter III. Instances where butenolides are used as dienophiles and Michael acceptors are also discussed. Dehydration followed by the Pd/C reduction of (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids is expected to give optically active Isocitric acid. Various reactions were tried to effect dehydration; which include the displacement of tertiary hydroxyl group with halogen and subsequent dehydrohalogenation. Interestingly the dehydration using phosphorous oxychloride in pyridine resulted in the isolation of an unusual dimethyl 3-methoxy 2(5H)-furanone 4,5-dicarboxylate and which was confirmed by IR, 1 H and 13 C NMR and mass spectroscopy. The structure of the compound was further ascertained with the help of DEPT and HMBC NMR studies. It was also observed that when the reaction was performed using diisopropyl ester of title compound, at elevated temperature formation of diisopropyl 2-(5H)- furanone-4,5- dicarboxylate has been observed. The dehydration of dialkyl (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5- oxo-2,3-furandicarboxylates with methanesufonyl chloride in triethylamine resulted in the formation of aromatic dialkyl- 5-[(methylsulfonyl) oxy]-2,3-

4 218 furandicarboxylate in quantitative yield irrespective of the alkyl substituent of the C2 and C3 carboxylic group. Formation of Dialkyl 3-methoxy 2(5H)- furanone 4,5-dicarboxylate was explained on the basis of crucial (2,3) sigmatropic rearrangement involving POCl 3. Enantiomerically pure1,2-diols and related substrates play significant role as chiral synthons in the synthesis of natural and biologically active molecules. Having two centers of chirality and vicinal diol moiety, trialkyl esters of (2S,3S)- and (2S,3R)-tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acids are expected to find extensive application in asymmetric reactions especially as chiral agents. Optically pure 1,2-diols (trialkyl (1S,2S)- and (1S,2R)- 1,2-dihydroxy1,2,3-propane tricarboxylates) were obtained from diastereomeric 2-hydroxycitric acids in quantitative yield. Starting from optically active dialkyl tartarates, Seebach and co-workers have prepared α,α,α,α -tetraaryl-1,3-dioxalane-4,5-dimethanols (TADDOLs) and applied them as efficient chiral agents in Diels Alder reactions, [2+2] Cycloadditions, Ene reactions. TADDOLs are also found to be efficient chiral dopants for converting nematic (achiral) liquid crystals to cholesteric(chiral) liquid crystals. Optically pure (4S,5S)-4-(2-Hydroxy-2,2- diarylethyl)-2,2-dimethyl-α,α,α,α -tetraaryl-1,3-dioxalane-4,5-dimethanols have been prepared from trimethyl (1S,2S)- and (1S,2R)-1,2- dihydroxy1,2,3-propane tricarboxylates. The TADDOL analogues thus obtained have been tested for their efficiency as chiral dopants in the phase transformation of nematic liquid crystal to cholesteric liquid crystals. An induction of cholesteric phase was observed by obtaining a finger print texture, charesteric of cholesteric liquid crystals by the addition of the TAADDOL analogue to an achiral liquid crystalline compound 4 -pentyl-4- biphenyl carbonitrile in the nematic phase. The efficiency of the chiral dopants is expressed in terms of helical twisting power of the chiral dopant and which needs further reflection studies.. Even though TADDOL

5 219 analogue obtained were found to be effective chiral dopants for the phase transformations of nematic liquid crystals into cholesteric liquid crystals, a detailed study in this direction is required to further explore their ferroelectric and piezo electric liquid crystal applications.