Sharma, Phani Krishna M.V.

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SynopsisSYNOPSISThe thesis entitled “Towards the Synthesis of Biologically Active Molecules: Zanamivir, Pinellic acid and (4R)–Dodecanolide” has been divided into four chapters.Chapter-I: This chapter has been further divided into two sections.Section A: This section deals with the introduction and previous synthetic approaches of Zanamivir. Section B: This section deals with the present work of Zanamivir. Chapter-II: This chapter has been divided into two sections.Section A: This section deals with the introduction, previous synthetic approaches of Pinellic acidSection B: This section deals with the present work of Pinellic acid. Chapter-III: This chapter has been divided into two sections.Section A: This section deals with the introduction and previous synthetic approaches of (4R)-Dodecanolide.Section B: This section deals with the present work of (4R)-Dodecanolide.Chapter-IV: This chapter has been divided into two sections.Section A: This sections deals with the brief review on BiCl3 and Imino Diels-Alder reactions. Section B: Stereoselective synthesis of octahydro-3b H-[1, 3] dioxolo [4'', 5'': 4', 5'] furo [2', 3': 5, 6] pyrano [4,3-b]- quinolines via intramolecular hetero-Diels-Alder reactions catalyzed by Bismuth (III) Chloride.Chapter I: Towards the synthesis of Zanamivir	Influenza viruses are the most serious viral cause of respiratory illness both in terms of morbidity and mortality, and influenza is a disease of immense economic importance. In 1918-1919 influenza is thought to have been responsible for the deaths of 20 million people. Influenza is also called the flu. It's an infection that causes fever (​http:​/​​/​kidshealth.org​/​kid​/​ill_injure​/​sick​/​fever.html​), chills, cough, body aches, headaches (​http:​/​​/​kidshealth.org​/​kid​/​ill_injure​/​sick​/​headache.html​), and sometimes earaches (​http:​/​​/​kidshealth.org​/​kid​/​ill_injure​/​sick​/​ear_infection.html​) or sinus problems (​http:​/​​/​kidshealth.org​/​kid​/​ill_injure​/​sick​/​sinuses.html​). The flu is caused by the influenza virus (​http:​/​​/​kidshealth.org​/​kid​/​talk​/​qa​/​germs.html​) A.	Zanamivir 1 inactivates viral influenza neuraminidase,1 an enzyme responsible for cleaving sialic acid residues on newly formed virions as they bud off from the host cell. This inhibition results in aggregation of virions on the surface of the host cell, which limits the extent of infection and speeds recovery from illness. Clinical studies have shown that neuraminidase inhibitors can decrease the median duration of influenza related symptoms by  1 day if initiated within 48 hours of the onset of symptoms of influenza. This section deals with the biological significance; clinical applications and gives brief account of the work carried out by the various research groups reported the total synthesis of Zanamivir.Our synthetic strategy is based on the inexpensive starting material D-Sorbitol which has three hydroxyl groups having same configuration as in side chain of the target molecule and permits characterization of the intermediates with simple techniques such as NMR, IR and Mass etc.Retrosynthetic strategy for ZanamivirThe synthesis of Zanamivir requires introduction of 2, 3 double bond and in particular a stereospecific introduction of nitrogen based substituents at C-4 and C-5 positions. The synthetic strategy that we adopted towards the total synthesis of Zanamivir started from inexpensive commercially available D-Sorbitol 7 as indicated in the following retro synthesis (Fig 2).Fig 2Present workD-Sorbitol 7 was converted to chiral propargyl alcohol 17 by the following sequence of reactions in a known route.2 Thus, D-Sorbitol 7 was treated with 37% formaldehyde solution in presence of conc. HCl to get tri methylene protected compound 8 in 68% yield (Scheme 1). The selective cleavage of 1, 3 and 5, 6-O-methylene groups of compound 8 was achieved with a mixture of acetic acid, acetic anhydride and conc. H2SO4 to get the tetra acetate 9 in 52% yield. The tetra acetate 9 was deacetylated with 0.2 N sodium methoxide in chloroform to afford the tetrol 10 in 60% yield. Scheme 1The tetrol 10 was converted to diacetonide 11 in 62% yield by using 2, 2-dimethoxy propane in presence of catalytic amount of PTSA in dry acetonitrile. The selective deprotection of 1, 3 -O-isopropylidene ring of 11 was achieved by using 30% acetic acid in methanol to provide the diol 12 in 60% yield. The primary hydroxyl group of compound 12 was protected as its silyl ether by using TBDMSCl and imidazole in dry DCM at room temperature to get compound 13 in 90% yield. The secondary hydroxyl group of compound 13 was protected as its PMB ether by using PMBBr and NaH in dry THF at room temperature for 4 h to afford the compound 14 in 85% yield. Compound 14 was subjected to deprotection of silyl group by using 1 eq of TBAF (1 M in THF) at 0oC to room temperature for 2 h to give alcohol 15 in 90% yield. The six membered 1,3-dioxolane alcohol 15 was converted to corresponding six membered 1, 3-dioxolane chloride 16 in 85% yield by using TPP and NaHCO3 in dry CCl4 on refluxing for 4 h. The chloro compound 16 was converted to 17 in 76% yield by using lithium metal and catalytic amount of ferric nitrate in liquid NH3.3Scheme 2The compound 17 was protected as its methoxy methyl ether 6 by using iPr2EtN, and MOMCl in dry DCM at room temperature for 20 h in 80% yield4 (Scheme 2). The ring opening of the epoxide 6a with alkyne 6 using n-BuLi (1.6 M, in hexane) and BF3.Et2O (Yamaguchi’s method) in dry THF at -78oC to gave the coupled product 5 in 70% yield.5 Controlled hydrogenation of the alkyne 5 to its cis alkene compound 18 in 90% yield, was achieved by using Pd/CaCO3 and quinoline (Lindlar’s catalyst) in EtOAc under H2 gas.  Oxidation of compound 18 by using Dess-Martin Periodinane in dry DCM for 30 min at room temperature afforded the compound 19 in 90% yield.6 The cyclized compound 20 was obtained by the deprotection of p-methoxy benzyl group in compound 19 by using DDQ, silica and DCM:H2O (9:1) in 70% yield.7 The cyclic compound 20 when treated with dry MeOH and catalytic amount of PPTS in dry DCM at room temperature for 6 h afforded 4 in 70% yield (Scheme 2). Scheme 3The compound 4 was converted to bromohydrin 21 (Dalton and Dutta method) as a single isomer by treating with NBS, water in DMSO at –10oC in 70% yield8 (Scheme 3). The base mediated cyclization of bromohydrin 21 using K2CO3 in MeOH at room temperature for 4 h furnished the epoxide 22 in 80% yield (Scheme 3). The epoxide 22 when opened by azide functionality using NaN3 and aq DMF at 125oC for 2 h afforded the mixture of regioisomers of azido alcohols 23 and 24 in 70% yield 9(Scheme 3). Generally nucleophile attacks from less hindered side, but in this case azide ion attacked abnormally and resulted in 70% yield of 23 and in 30% yield of 24. The secondary hydroxyl groups of azido alcohols 23 and 24 were converted as their mesylates 25 and 26 respectively in 90% yield using MeSO2Cl and TEA in dry DCM at 0oC. The stereochemistry of azide and –OMs groups were characterized by nOe studies. Mesylazide compounds 25 and 26 were treated with TPP and iPr2EtN in aq THF at reflux temperature to give aziridine 27 in 85% yield. The ring opening of the aziridine 27 was demonstrated with sodium azide and aq DMF at 125oC. After purification the compound was acetylated with acetic anhydride, Et3N and catalytic amount of DMAP in dry DCM to get 3 in 70% yield (Scheme 3). The ring opening of aziridine 27, unlike epoxide 22 as indicated by nOe studies underwent nuceleophile attack from less hindered side. Nucleophilic attack from more hindered side would have resulted in desired stereochemistry to complete the synthesis of Zanamivir effectively, efforts are still on for the total synthesis of Zanamivir. Chapter II: Total synthesis of Pinellic acid Pinellic acid10 (28) isolated from an oriental medicine, pinellae tuber, is a novel and potentially useful oral adjuvant when used in conjunction with intranasal inoculation of influenza HA vaccines Pinellic acid Fig 3	Among the C-9-isomer of Pinellic acid, 9S-compound showed much stronger activity compared with 9R-compounds. Thus stereochemistry at the C-9 hydroxyl group is very important for adjuvant activity. Among the 9S-derivatives, the adjuvant activities of 13S-compounds are stronger than that of 13R-compounds. However, the stereochemistry of the C-12 hydroxyl group is not important for adjuvant activity.Retrosynthetic strategy for Pinellic acid	We chose a strategy for the synthesis of Pinellic acid 28 by disconnecting the carbon backbone at C11-C12, thus dividing the target into two key fragments 30 and 31. Both C1-C11 fragment 30 and C12-C18 fragment 31 possess a common precursor 33, which with respective alkyl halides results in corresponding compounds (Fig 4).Fig 4Construction of the C12-C18 fragment Initially propargyl alcohol 33 was treated with 1-bromo pentane 34 in liquid ammonia using lithium amide at –33oC to give compound 35 in 65% yield.11 Acetylenic alcohol 35 was reduced with LiAlH4 in refluxing dry THF to afford the trans -allylic alcohol 36 in 90% yield. The E-allyl alcohol 36 was subjected to Sharpless asymmetric epoxidation protocol. Accordingly, treatment of 36 with L (+) DET, Ti (OiPr)4 and TBHP (3.3 M in toluene) in dry DCM at -24oC afforded the epoxy alcohol 37 in 80% yield.12 The epoxy alcohol 37 was converted to corresponding epoxy iodide 38 in 80% yield using triphenylphosphine, iodine and imidazole in a mixture of dry ether and acetonitrile in 3:1 ratio at room temperature (Scheme 4).Scheme 4Compound 38 were converted into a secondary allylic alcohol 39 in 80% yield by refluxing with activated zinc and sodium iodide in dry methanol.13 The allylic compound 39 was converted into methoxy methyl ether 40 in 90% yield using Hunig’s base iPr2NEt and MOMCl for 2 h at room temperature. The compound 40 was subjected to ozonolysis to give the required aldehyde 31 in 80% yield (Scheme 4). Construction of C1-C11 fragmentThis fragment was synthesized by following a known route. Propargyl alcohol 33 was treated with bromide 32 in lithium amide at liquid ammonia temperature to give compound 41 in 70% yield. Acetylenic alcohol 41 was reduced with LiAlH4 in refluxing dry THF to afford the trans-allylic alcohol 42 in 80% yield. The E-allyl alcohol 42 was subjected to Sharpless asymmetric epoxidation protocol. Accordingly, treatment of compound 42 with L (+) DET, Ti(OiPr)4 and TBHP (3.3 M in toluene) in dry DCM at -24oC afforded the epoxy alcohol 43 in 80% yield. The epoxy alcohol 43 was converted to corresponding epoxy chloride 44 in 90% yield by using TPP and NaHCO3 in dry CCl4 on refluxing for 4 h. Accordingly compound 44 was subjected to lithium amide in liquid ammonia to get the chiral propargyl alcohol 45. The secondary hydroxyl functionality of compound 45 was protected as its methoxy methyl ether using Hunig’s (iPr2EtN) base and MOMCl in dry DCM at room temperature to afford the compound 30 in 90% yield (Scheme 5).Scheme 5Coupling of C1-C11 and C12-C18 fragments Compound 31 was treated with n-BuLi, HMPA and coupled with aldehyde 31 at -78oC to get compound 29 (20:1) in 75% yield. The coupled compound 29 was treated with LAH to afford trans-allyl alcohol 46 in 80% yield. Scheme 6The secondary hydroxyl functionality of compound 46 was protected as its methoxy methyl ether using Hunig’s (iPr2EtN) base and MOMCl in dry DCM at room temperature to afford the compound 47 in 90% yield. THP deprotection of 47 was carried out by using PPTS in methanol to afford the compound 48 in 80% yield.14 The compound 48 was oxidized with DMP in DCM to afford the aldehyde 49 in 85% yield (Scheme 6). The compound 49 was further oxidized with NaClO2 and NaH2PO4 in DCM to afford the corresponding acid 50 in 79% yield.15 Finally deprotection of three MOM groups by using 6 N HCl to afforded the target molecule 28 in 70% yield (Scheme 6).Chapter III: Total synthesis of (4R)-DodecanolideLactonic functionality is present in a large number of natural products and biologically active compounds. Lactone derivatives are very common flavor components16 used in the perfume industry. They have also been reported to be sex attractant pheromones of different insects and to be plant growth regulators and they are also useful intermediates in the synthesis of natural products.Fig 5 	(4R)-Dodecanolide is a pheromone component, which was isolated from the pygidal glands of rove beetles Bledius mandibularies and Bledius spectabilis by Wheeler et al. Retrosynthetic route of (4R)-DodecanolideThe synthetic strategy adopted for the synthesis of (4R)–Dodecanolide is outlined below (Fig 6).Fig 6Present workInitially propargyl alcohol 33 was treated with 1-bromooctane 55 in liquid ammonia using lithium amide at -33oC to give compound 56 in 75% yield. Scheme 7Acetylenic alcohol 56 was reduced with LiAlH4 in refluxing dry THF to afford the trans-allylic alcohol 57 in 85% yield The E- allyl alcohol 57 was subjected to the Sharpless asymmetric epoxidation protocol. Accordingly, treatment of compound 57 with D (-) DET, 0.2 eq of Ti (OiPr)4 and TBHP (3.3 M in toluene) in dry DCM at -24oC afforded the epoxy alcohol 58 in 85% yield. The epoxy alcohol 58 was converted to corresponding epoxy chloride 59 in 90% yield by using TPP and NaHCO3, in dry CCl4 on refluxing for 4 h. Accordingly, compound 59 was subjected to LiNH2 in liquid ammonia to get the chiral propargyl alcohol 60 in 76% yield (Scheme 7). The secondary hydroxyl functionality of 60 was protected as its methoxy methyl ether using Hunig’s base (iPr2EtN) and MOMCl in dry DCM at room temperature to afford 53 in 90% yield (Scheme 7). The acetylene 53 was subjected to methoxy carbonylation in presence of 1 eq of n-BuLi (1.6 M in Hexane) and 1 eq of 54 at -78oC to give the compound 61 in 90% yield.17 The ester 61 was reduced with 10% Pd/C under hydrogen atmosphere to get the saturated ester 52 in 90% yield (Scheme 7). Finally the Cyclization of 2 with PTSA in methanol afforded 51 in 85% yield (Scheme 7). Chapter IV: BiCl3 Catalyzed Intramolecular imino Diels-Alder reactions.Stereoselective synthesis of octahydro-3b H-[1, 3] dioxolo [4'', 5'': 4', 5'] furo [2', 3': 5, 6] pyrano [4,3-b]- quinolines via intramolecular hetero-Diels-Alder reactions catalyzed by Bismuth (III) Chloride.The chemistry of tetrahydroquinoline derivatives has been long area of intense for organic chemists due to presence of these scaffolds within the framework of numerous biologically interesting natural products and pharmaceutical agents. The most attractive strategy for these derivatives is the acid-promoted imino-Diels-Alder reaction between N-arylaldimines and electron rich alkenes. Carbohydrates have been used as chiral auxiliaries or chiral building blocks and used in asymmetric transformations due to their known absolute stereochemistry, readily availability and often their low cost.18 In continuation of our interest on intramolecular hetero-Diels-Alder reactions, we report herein BiCl3 catalyzed highly efficient and stereoselective synthesis of 2,2,6,6-tetramethyl3a,5,5a,6,11,11a,11b,12a-octahydro-3bH 1,3]dioxolo[4'',5'':4',5']furo[2',3':5,6] pyrano[4,3-b]quinolines using [4+2] cycloaddition reactions of anilines with the O-allyl derivative of the sugar derived  aldehyde19 63 from D-glucose (Scheme 8).Scheme 8The reaction of aniline 62a with the O-allyl derivative of the aldehyde 63 in acetonitrile in the presence of 10 mol% BiCl3 furnished a diastereomeric mixture of trans and cis products 64 and 65 in 93:7 ratio in 81% yield. The reaction was very rapid and complete in 30 minutes as indicated by TLC. The structure of compound confirmed by inter proton-coupling constants and characteristic nOe’s were used to obtain the proposed structures. These structures were further supported by minimum energy calculations.23 Under similar conditions, several aromatic amines 62a-i were treated with the O-allyl derivative 63 to illustrate the novelty of the present strategy and the results are presented in the Table 2. In all cases the reactions are highly stereoselective, leading to the formation of trans isomers as the major products and cis isomers as minor products. When a bulky group such as tert-butyl is presenting to ortho to the amine (entry 3) only one diastereomer was isolated.References:1). Ryan, D. M,; Ticehurst, J,; Dempsey, M. H,; Penn, C. R. Antimicrob. Agents Chemother. 1994, 38, 2270. 2). Hann, R. M.; Ness A. T.; Hudson, C. S. J. Am. Chem. Soc. 1944, 66, 73.3). Yadav, J. S.; Madhavi, C.; Srinivas Rao, C. Tetrahedron Lett. 1989, 30, 5455.4). Stork. G.; Takahashi. T. J. Am. Chem. 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Tetrahedron Lett. 1981, 37, 2091.16). a) Willhalm, B.; Palluy, E.; and Winter, M. Helv. Chem. Acta. 1966, 49, 66. b) Broderick. Am. Perfumer. Cosmet. 1966, 86, 43. c) Tang, C. S.; and Jennigs, W. G. J. Agr. Food. Chem. 1968, 16, 252.17). Nakata, M.; Ohashi, Junji.; Ohsawa, K.; Nishimura, T.; Kinoshita, M.; Tatsuta, K. Bull. Chem. Soc. Jpn. 1983, 66, 3464.18). Hultin, P. G., Earle, M. A.; Sudarshan, M. Tetrahedron 1997, 53, 14823.19). Sharma, G. V. M.; Srinivas Reddy, I.; Goverdhan Reddy, V.; Rama Rao, A. V. Tetrahedron: Asymmetry 1999, 10, 229. EMBED ChemDraw.Document.4.0  PAGE  I 

Study and development of TIO2 - based photocatalysts for pesticide degradation

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Study and development of TIO2 - based photocatalysts for pesticide degradation

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