Abstract ABSTRACT The thesis entitled “Novel electrophiles, bases and synthetic utility of Baylis-Hillman reaction; synthesis of syn, anti, syn stereotetrad building block and TosMIC mediated synthesis of amides” is divided into three chapters. Chapter I: Novel electrophiles, bases in Baylis-Hillman reaction and synthetic utility of Baylis-Hillman adducts. Section A: This section dealt with the acetylenic aldehydes as electrophiles, NMM and Urotropine as bases in Baylis-Hillman reaction. Part I: This part of section exploits the use of acetylenic aldehydes as novel electrophiles in Baylis-Hillman reaction. The Baylis–Hillman reaction is one such interesting reaction, which involves the selective atom-economical construction of a carbon–carbon bond at the -position of an activated alkene, providing densely functionalized molecules. This reaction has earned overwhelming synthetic popularity in recent years as evidenced by the publication of several reviews 1,2 and a large number of research papers. Although there is considerable progress in designing and synthesizing various three essential components such as electrophiles, activated olefins and catalysts (bases), to date there is a challenge to develop the above components for buildup multi functionalized molecule which are useful and needful either in biological activity systems or precursors to biological acive complexes in nature. For instance, Bhat and co-workers3 investigated the antimalarial activity of 3-hydroxy-3-aryl(heteroaryl)-2- methylenepropanenitriles (Baylis-Hillman adducts derived from acrylonitrile and aryl or heteroaryl aldehydes) and found that adducts 1-3 (Figure 1) were shown to have antimalarial activity against P. falciparum in vitro. 2-(hydroxymethyl)cyclohex-2-enone (the Baylis- Hillman adduct obtained from cyclohex-2-enone and formaldehyde) has been used in the preparation of 2-crotonyloxymethyl-2-cyclohexenone (COMC) (biologically active molecule) by Creighton and coworkers.4 They hypothesized that COMC is an enzyme activated prodrug in which the crotonate ester serves as a leaving group, in a process triggered by glutathionyl transferase (Scheme 1). 1 Abstract OH OH OH CN MeO CN CN MeO O2N N OMe 1 3 2 Figure 1 Similarly, Lin et al.5 synthesized a new class of pyrimidinyl agents using the Baylis-Hillman strategy and studied their in vitro antimalarial activities against Plasmodium falciparum. Out of all these molecules, the compound 4 exhibits the most antimalarial activity, which is comparable to that of chloroquine including several works6 has been carried out until now (Figure 2). O O OH crotonic anhydride py, DMAP, rt OCOCH=CH-CH3 GSH glutathionyltransferase GS O COMC Scheme 1 N O O Ph OAc O N H N O N H OMe O 4 Figure 2 In the course of our study on Baylis-Hillman reaction,7 the development of electrophile such as acetylenic aldehydes has been explored for carbon-carbon bond formation to construct functionalized molecule (Scheme 2). Accordingly, the acetylenic aldehydes were prepared by known procedure8 from simple alkynes through formylation. Initially, we examined Baylis-Hillman reaction of phenyl acetylenic aldehyde 1 with common known activated alkene ethyl acrylate 4 to afford 7 in 45% yield but the same reaction was completed within short time in DMSO in the presence of 50 mol% of DABCO giving a 74% yield of the product 7. Thus obtained product 7 in the above was confirmed by its spectral data. 2 Abstract O R CHO + DABCO, DMSO R1 R = 1.C6H5, 2. n-C6H13 3. BnO-(CH2)2- RT, 15 h 58-80% 24 - 44% de R1 = 4. OEt 5. CH3 6. Sug O Sug = O O O O O Scheme 2 OH O R R1 7. R = C6H5, R1 = OEt 8. R = C6H5, R1 = CH3 9. R = C6H5, R1 = Sug 10. R = n-C6H13, R1 = OEt 11. R = n-C6H13, R1 = CH3 12. R = n-C6H13, R1 = Sug 13. R = BnO-(CH2)2-, R1 = OEt 14. R = BnO-(CH2)2-, R1 = CH3 15. R = BnO-(CH2)2-, R1 = Sug In the same way, we performed the Baylis-Hillman reaction of phenyl acetylenic aldehyde 1 with methylvinyl ketone 5 under optimized reaction conditions to result in 8 (67%). On the other hand, after getting good results with simple and common olefins, our next aim was to construct the sugar molecule with sugar auxillary as as chiral olefin 6, which on reaction with the aldehyde 1 gave the desired Baylis-Hillman adduct 9 as a product in 58% yield and in moderate diastereoselectivity with 30% as determined from 1 H NMR spectrum. Later, the remaining acetylenic aldehydes such as 2-nonynal 2 and 5-benzyloxy- 2-pentynal 3 have also been used with ethyl acrylate 4, methylvinyl ketone 5, and sugar acrylate 6, under optimized conditions to afford the product 10 (80%), 11 (59% yield), 12 (61% yield) and in 44% diastereoselectivity obtained, in the case of aldehyde 3 gave compound 15 with 24% diastereoselectivity of the adduct with sugar acrylate 6, apart from 13 in 75% yield and 14 in 61% yield respectively. In conclusion, it has successfully been demonstrated that acetylenic aldehydes can be used in Baylis-Hillman reaction for the synthesis of allyl propargyl alcohols. Part II: This part of section exploits the use of NMM and Urotropine as bases in BaylisHillman reaction. Catalysts used often are very substrate specific9 and the results are also very sensitive to precise reaction conditions.10 The most common catalyst for Baylis-Hillman reaction is 1,4-diazabicyclo [2.2.2]octane (DABCO). However, DABCO was found to be ineffective to many substrates.11 For instance, in the coupling of cyclohexenone with 3 Abstract formaldehyde12 DABCO is not a reagent of choice. Though DMAP, 13 DBU,14 and tetramethylguanidine9 (TMG) are known in literature as catalysts for Baylis-Hillman reaction. It is very challenging task to identified and build up various inexpensive bases (catalysts) in Bayli-Hillman reaction. Thus, N-Methylmorpholine ( C5H11NO, NMM) is a inexpensive flammable liquid chemical with a pungent smell and, is a commercially available milder base and, has been isolated15 from the seeds of Cassia occidentalis L. (coffee senna) belonging to leguminacae family. It is widely useful solvent16 for resins, waxes, dyes, casein, and used in peptide synthesis17 to minimize racemization as a base, as a deprotecting agent18 for Fmoc, in heterocyclization of thiosemicarbazides. Similarly, Urotropine (C6H12N4), is flammable white crystalline solid and is commercially very inexpensive chemical, and is also called as hexamine/hexamethylinetetraamine. It can be easily prepared from the condensation19 of ammonia and formaldehyde. It is used as a reagent in ring-closure reaction, synthesis of triaza-, tetraaza- heterocyclic derivatives,19,20 and has been used as a base in BaylisHillman reaction,21 in α-methylation of aryl alkyl ketones,22 and mostly used in the preparation of trimethylenetrinitramine (RDX).23 Consequently, the Baylis-Hillman reaction was performed for standardization of reaction conditions between 4-nitrobenzaldehyde 17 and ethyl acrylate 4 in different solvents such as THF (0% yield with NMM and urotropine), DMF (39% yield with NMM and 56% with urotropine), DMSO (48% yield with NMM and 69% with urotropine), sulpholane (0% yield with NMM and 80% with urotropine) and dioxanewater (1:1) using stoichiometric amounts of NMM and urotropine at ambient temperature. An optimum yield of adduct 22 73% with NMM and 95% with urotropine was obtained when the reaction was run for 24 h in a 1:1 mixture of 1, 4-dioxane-water.24 However, when the catalyst loading was decreased to 50 mol% or 25 mol% there was significant reduction of the yields This amply demonstrates the necessity of stoichiometric amounts of NMM and urotropine for catalyzing Baylis-Hillman reaction. Subsequently, ethyl acrylate was also treated with other aldehydes (Scheme 3). Accordingly, 2-nitrobenzaldehyde 18 and phenyl acetylenic aldehyde 19 reacts with ethyl 4 Abstract acrylate 4 to result in the adducts 25 in 62% and 92% with NMM and urotropine and 29 in 69 and 76% yields respectively. R CHO + 17. R = 4-NO2-Ph, OH NMM or Urotropine EWG EWG R Dioxane: H2O (1:1) or, DMSO, r.t., 16-48 h 22. R = 4-NO2-Ph, EWG = CO2Et 23. R = 4-NO2-Ph, EWG = COCH3 EWG = 4. CO2Et, 24. R = 4-NO2-Ph, EWG = CN 18. 2-NO2-Ph, 5. COCH3, 25. R = 2-NO2-Ph, EWG = CO2Et 19. Ph 16. CN 26. R = 2-NO2-Ph, EWG = COCH3 20. Ph 27. R = 2-NO2-Ph, EWG = CN 28. R = Ph, EWG = CN O R CHO OH O NMM or Urotropine + R Dioxane: H2O (1:1) r.t., 20-36 h R = 17, 18 and 21 (H) 22 29. R = Ph EWG = CO2Et 30. R = Ph EWG = COCH3 31.R = Ph EWG = CN 32. R = H 33. R = 17 34. R = 18 Scheme 3 Table 1: Reactions of various aldehydes with olefins by using NMM and Urotropine Urotropine Time (h) Entry Aldehyde Alkene Solvent NMM Time (h) 1 17 4 Dioxane-H2O 24 22, 73 24 22, 95 2 18 4 Dioxane-H2O 36 25, 62 34 25, 92 3 20 4 Dioxane-H2O 24 29, 69 24 29, 76 4 17 5 DMSO 24 23, 68 20 23, 85 5 18 5 DMSO 36 26, 62 28 26, 73 6 20 5 DMSO 24 30, 72 16 30, 84 7 17 16 Dioxane-H2O 24 24, 98 20 24, 99 8 18 16 Dioxane-H2O 36 27, 96 24 27, 99 9 20 16 Dioxane-H2O 24 31, 88 18 31, 91 10 19 16 Dioxane-H2O 48 28, 64 35 28, 71 11 17 22 Dioxane-H2O 24 32, 71 20 32, 83 12 18 22 Dioxane-H2O 36 33, 63 24 33, 68 13 21 22 Dioxane-H2O 36 34, 60 32 34, 62 5 Yield (%) Yield (%) Abstract Simultaneously, the other activate olefins such as methylvinyl ketone 5 and acrylonitrile 16 also reacted with the above aldehydes 4-nitrobenzaldehyde 17, 2nitrobenzaldehyde 18 and phenyl acetylenic aldehyde 19 under this reaction conditions to afford corresponding Baylis-Hillman adducts in moderate to good yields (Table 1). In the case of acrylonitrile 16, simple benzaldehyde 20 was also gave a desired product in good yields with NMM (64%) as well as urotropine (71%). Likewise, aldehydes 4-nitrobenzaldehyde 17, 2-nitrobenzaldehyde 18 including simple formaldehyde 21 under went Baylis-Hillman reaction under the present reaction conditions with cyclohex-2-enone 22 to produce the adducts 33 (63 and 68% yields), 34 (60 and 62% yields), 32 (71 and 83% yields) respectively. In conclusion, we have successfully introduced inexpensive and comercially available N-methylmorpholine (NMM) and urotropine as new base catalysts for the Baylis-Hillman reaction at ambient temperature in aqueous dioaxne (1:1) to afford adducts in reasonably good yields. Section B: Lewis Acid and/or Lewis Base catalyzed [3+2] cycloaddition reaction: Synthesis of pyrazoles and pyrazolines This section dealt with the utility of Baylis-Hillman adducts including simple activated olefins in [3+2] cycloaddition reactions in the presence of Lewis acid (InCl3) and Lewis base (DABCO). Cycloadditions of nitrogen-containing dipoles with olefinic dipolarophiles continue to be attractive for the synthesis of a variety of heterocycles.25 Synthesis of pyrazolines has been stimulated by the fact that some of their derivatives were found to possess important bioactivities. Especially their antimicrobial,26 immunosuppressive27 and central nervous system activity28 should be emphasized. Although pyrazolines are useful substances in drug research and are well-known five-membered nitrogencontaining heterocyclic compounds, a comprehensive review on their synthesis was published thirty years ago.29 However, the pyrazole substructure appears in small 6 Abstract molecules which possess a wide range of biological activities, and accordingly represents a valuable target for organic synthesis.30 Owing to the importance of the five membered carbocyclic or heterocyclic molecules, and, in the continuation of our work on Baylis-Hillman reaction and utility of their adducts, we envisaged a development of [3+2] cycloaddition reaction with BaylisHillman adducts including some commercially available olefins (Scheme 4). R EWG R = H, CH2OH, alkyl, aryl EWG = CO2Et, CN, etc CO2Et N2CHCOOEt 35 EWG DABCO (Method A)/ InCl3 (Method B) neat, rt Scheme 4 R N H N . Accordingly, in our initial study, we found that DABCO effectively catalyzes pyrazoline formation from simple Michael acceptor/electron poor olefin 4 ethyl acrylate and ethyl diazoacetate 35 in 97% yield in 2 h at ambient temperature (Scheme 5). For this protocol various solvents were examined and the maximum yield was obtained under neat conditions at short time. Subsequent to these preliminary investigations, the effects of different Lewis acids/and bases on the [3+2] cycloaddition reaction was examined and concluded that InCl3 and DABCO act as best Lewis acid and base respectively for cycloaddition reactions. Further, known olefin, ethyl acrylate 4 undergoes a facile [3+2] cycloaddition with ethyl diazoacetate 35 in the presence of DABCO (Method A) and Lewis acid InCl3 (Method B) independently to result in which substituted pyrazoline derivative 43 in 97% yield with DABCO as well as 80% yield with InCl3 respectively. In similar manner, the other olefins such as acrylonitrile 16, N,N-dibenzyl acrylamide 36 and 4acryloylmorpholine 37 underwent reaction to afford the pyrazoline ring systems like 44 (52 and 46% yields), 45 (69 and 56% yields), 46 (58 and 49% yields) respectively with both the methods absolutely (Table 2). Our next aim was to construct the heterocyclic rings with different types of Baylis-Hillman adducts (Table 3). Accordingly, ethyl 2-[hydroxy(phenyl)methyl]acrylate 38 with ethyl diazoacetate 35 gave substituted pyrazoline derivatives by both the methods in 75 and 60% yields respectively. In the same manner, the other adducts such as ethyl 2- 7 Abstract [hydroxy(4-nitrophenyl)methyl]acrylate 39, 2-[hydroxy(2-nitrophenyl)methyl]acrylate 40, diethyl 5-(1-hydroxyhexyl)-4,5-dihydro-1H-3,5- pyrazoledicarboxylate 41, ethyl 2(hydroxymethyl) acrylate 42 were also reacted to result in corresponding pyrazoline Table 2: Ethyl diazoacetate reaction with simple olefins with InCl3 and DABCO. Dipolarophile Entry Method Product CO2Et CO2Et 1 EtO2C 4 N H N CN NC 16 N H O NBn 2 3 N Bn 2N 36 N H N O N 4 37 N O N H 2 97 B 4 80 A 6 52 B 10 46 A 4 69 B 8 56 A 5 58 B 7 49 45 CO2Et O A 44 CO2Et O Yield (%) 43 CO2Et 2 Time [h] N 46 O Table 3: Ethyl diazoacetate reaction with Baylis-Hillman adducts with InCl3 and DABCO. Entry Dipolarophile Product Method OH OH CO2Et CO2Et Time [h] Yield (%) A 6 75 B 8 60 A 2 95 B 5 78 A 2 86 B 5 66 A 3 85 B 7 61 A 4 B 7 N 1 N EtO2C H 47 38 OH OH CO2Et CO2Et 2 N O2N N EtO2C H 48 39 O2N OH OH CO2Et CO2Et 3 NO 2 40 N NO 2 N EtO2C H 49 OH H3C 4 4 CO2Et 41 OH CO2Et 5 42 CO2Et OH H3C N 4 N EtO2C H 50 CO2Et OH EtO2C N N H 51 8 82 71 Abstract derivatives like 48 (95 and 78% yields), 49 (86 and 66% yields), 50 (85 and 61% yields), 51 (82 and 71% yields) respectively by both the methods A and B respectively. Thus, obtained results motivated us to be apply this reaction on simple alkynes such as phenyl acetylene 52 and activated alkyne 53 with ethyl diazoacetate 35 to construct pyrazoles in moderate to good yields (Scheme 5). O CO2Et EtO OEt 56 O N2CHCO2Et Method A neat, rt N2CHCO2Et Method B neat, rt EtO2C 53 EtO2C N N H 55 CO2Et N2CHCO2Et Ph 52 Method A or B neat, rt Ph N H N 54 Scheme 5 As illustrated in the above scheme ethyl diazoacetate 35 when react with phenyl acetylene 52 in both the reaction conditions to afford the pyrazole 54 in 64% and 53% yields with DABCO and InCl3 respectively, in the case of ethyl propiolate 53 on reaction with ethyl diazoacetate 35 resulted the pyrazole 55 in 66% yield only in the presence of Lewis acid InCl3, but resulted the dimer 56 of ethyl propiolate in the presence of DABCO. In conclusion, a simple, general one-pot protocol for the synthesis of heterocyclic 3,5-disubstituted pyrazolines and pyrazoles was developed under mild conditions in good to excellent yields from Baylis-Hillman adducts including different type of electron poor and simple alkynes are also tolerated in this reaction. Chapter II: Synthesis of syn, anti, syn stereotetrad building block This chapter dealt with the linear synthesis of syn, anti, syn stereotetrad from simple homopropargylic alcohol as a useful building block in the synthesis of biologically active systems such as pironetin The polyketides constitute an important family of natural products having a broad spectrum of biological activity such as antibiotic, antitumor, antifungal, antiparasitic, or 9 Abstract immunomodulatory action.31 Many of these compounds are referred to as polypropionates32 (systems possessing units with alternating hydroxyl and methyl groups), reflecting their common biosynthesis from propionate and, to a lesser extent, acetate units.33 The importance of these natural products as therapeutic agents and as biomedical tools together with their structural complexity has made these molecules attractive targets for synthetic organic chemists for over two decades.34 The key to construct these systems, which possess a high level of stereochemical information, is the O OMe OPG O O II OMe OH O Evan's aldol O O Et OMe OR 1 RCM Et + N Bn Et I O R2 III IV R1 = MOM R2 = CHO OMe OR 1 O TBDPSO OEt OH 67 3-Butyn-1-ol 57 Aldol OR 1 TBDPSO R2 O OH TBDPSO R1 = H 66 60 OR 1 OR 1 TBDPSO R1 = PMB R2 = CH2OH 63 + CH3CO2Et R1 = PMB R2 = CHO Hydroboration TBDPSO R2 65 Grignard reaction Epoxide ringopening Tebbe's reaction Scheme 6 control of the absolute and relative stereochemistry. Towards this goal and an attempt to total synthesis of pironetin35 (PA-48153C) we approached linear synthetic method that included the key steps such Sharpless asymmetric epoxidation, stereo- and regioselective ring-opening of epoxide and hydroboration of the olefin which was accessed through Tebbe’s reaction as a key steps including an EtOAc addition on the stereotriad to obtain an advanced intermediate. 10 Abstract The retrosynthetic analysis, as depicted in Scheme 6, reveals that the stereotetrad 67 can be accessible from ethyl acetate and triad 66 by aldol reaction selectively with LiHMDS. Meanwhile, the triad 66 can be achieved from formylation of simple terminal alkyne 57 following Lindlar’s catalytic cis-olefination, Sharpless asymmetric epoxidation, stereo- and regioselective ring-opening of epoxide and hydroboration of the olefin that was earlier accessed through Tebbe’s reaction as some of the key steps. Accordingly (Scheme 7), homo propargylic alcohol 57 was converted to TBDPS ether which was further subjected to produce propargylic alcohol 58 by formylation. 60 in turn was obtained from the compound 58 on reaction of selective catalytic reduction in the presence of 5% Pd/BaSO4 and quinoline (5 wt%), which on asymmetric Sharpless epoxidation of cis-olefin resulted in hydroxyl epoxide 60 in 94% yield (92% ee). Then the resulting hydroxyl epoxide 60 was subjected to oxidation with NaIO4 in the presence of catalytic amounts of RuCl3 in CCl4:CH3CN:H2O (1:1:1.5) at ambient temperature to furnish carboxylic acid,36 which further underwent highly regioselective and efficient, incorporation of the methyl group stereoselectively to afford 61 (80%). Thus obtained hydroxyl acid 61 was converted into methyl ester and the ester was reduced to give diol 62 under known conditions. Later this diol 62 was converted into dioxalane derivative with anisaldehyde dimethyl acetal in the presence of cat. PTSA followed by a regioselective reductive ring-opening to give PMB ether 63 in good yields. Compound 63 on oxidation followed by Grignard reaction with CH3MgI yielded secondary alcohol 64. The stereotriad 66 was obtained by oxidation of 64, and converting thus obtained ketone into olefin 65 with Tebbe’s reagent in good yield, which then prompted to hydroboration with dicyclohexylborane resulted in stereotriad 66 as a exclusively product with a free primary alcohol. This alcohol 66 on further oxidation with IBX resulted an aldehyde which in turn formed a stereotetrad 67 by addition of EtOAc to aldehyde in the presence of LiHMDS with good yield as an exclusive Felkin product.37 The exclusive formation of 1,3-anti and 1,2-syn product in the EtOAc addition to afford product 67 in Scheme 7 can be explained by presuming both the Felkin-Anh rule and the Zimmerman-Traxler model.37 In the case of Z(O)-enolates, the Felkin-type transition states leading to 67 suffer from severe 1,3-syn-pentane (cf. I) or gauche (cf. II) interactions. In contrast, the anti-Felkin transition state III minimizes both 1,3-syn-pen- 11 Abstract OH OTBDPS a, b c 57 d OTBDPS HO HO 59 58 O e, f OTBDPS HO g, h HO O OTBDPS OH 60 HO OTBDPS OH 61 62 OH k, l i, j HO m, n OTBDPS H3C OPMB OTBDPS o 64 65 p, q HO OTBDPS r, s EtO2C OTBDPS OH OPMB OPMB 66 EtO2C OTBDPS OPMB OPMB 63 H3C 67 OTBDPS OH OMOM 68 Scheme 7 Reagents: (a) TBDPSCl (1.1 equiv), imidazole (2.2 equiv), CH 2Cl2, 25 °C, 16 h, 99%; (b) EtMgBr (3 equiv), p-formaldehyde (3 equiv), THF 0oC-25 °C, 18 h, 71%; (c) H2 (1 atm), 5% Pd/BaSO4 (7 wt %), quinoline (5 wt %), MeOH, 25 °C, overnighht, 98%; (d) Ti(OiPr)4 (0.1 equiv), L-DIPT (0.2 equiv), CHP (1.0 equiv), MS (4 Å), CH2Cl2, -20 °C, 24 h, 99%, 92% ee ; (e) NaIO4 (4.1 equiv), RuCl33H2O (2.2 mol %), CCl4/CH3CN/H2O (1:1:1.5), 25 °C, 4 h, 80%; (f) AlMe3 (3.0 equiv), hexane, 25 °C, 40 h, 75%; (g) MeI (1.3 equiv), K2CO3 (1.0 equiv), acetone, 25 °C, 18 h, 90%; (h) LAH (1.2 equiv), THF, 0 oC, 1h, 84%; (i) Anisaldehyde dimethyl acetal (1 equiv), PTSA (cat), CH2Cl2, 98%; (j) DIBAL (1.5 equiv), CH2Cl2, 0 oC-25 o C, 98%; (k) DMSO (4 equiv), (COCl)2 (2 equiv), Et3N (8 equiv), CH2Cl2, -78 oC, 30 min, >99% (crude oil); (l) MeMgI (3 equiv), ether, 0 oC-25 oC, 3 h, 94 %; (m) Dess-Martin periodinane (1.5 equiv), solid NaHCO3 (1.2 equiv), CH2Cl2, 0 oC, 4 h, 96%; (n) Tebbe reagent (1.1 equiv), THF, 0 oC, 2 h, 88%; (o) BH3DMS (3 equiv), cyclohexene (6 equiv), THF, 0 oC-25 oC, 4 h, 86%; (p) IBX (1.5 equiv), DMSO, 0 oCrt, 4 h, 76%; (q) HMDS (4.2 equiv), n-BuLi (4.2 equiv), EtOAc (4 equiv), THF, -78 oC, 2 h, 74%; (r) MOMCl (2 x 2 equiv), DIPEA (5 equiv), CH 2Cl2, 0 oC-reflux, 2-4 h, 82%; (s) DDQ (1.2 equiv), CH2Cl2:H2O (8:0.4 mL), 25 oC, 40 min, 91%. tane and gauche interactions, leading to anti, anti aldol product as anti-Felkin product predominantly (Figure 4). In contrast, E(O)-enolates, should preferentially give rise to the Felkin adduct 67 The transition state V leading to the anti-Felkin product, which suffers from a gauche interaction between R and L compared to the Felkin transition state IV, in which only a gauche interaction between R and M is evident (Figure 5). On the other hand, during the addition of EtOAc to aldehyde the experience of all the interactions are suppressed because herein R group is a simple hydrogen therefore the transition states III and V are ruled out. However, the transition state II has some of 12 Abstract X Lig Met H O H H L O X Lig Lig Met H O H L M R Lig O R M H 1,3-syn-pentane interaction gauche interaction I II L M Lig Met X O H Lig O H R anti-Felkin transitionstate III Figure 4 the Gauche interactions between H and L groups and hence this transition state also not suitable when compared to transition states I and IV where all the interactions are absent except in the transition state I which shows 1,3-syn-pentane interactions between hydrogen, H and M is negligible to form Felkin product predominantly and exlusively. Hence, of the two I and IV, the later transition state is more preferred to invoke and explain the anti, syn aldol product formation in the above reaction. X Lig Met H O R H L O M H Lig Lig Met X O R O Lig L H H M gauche interaction unfavorable leads to Felkin product IV V Figure 5 Thus, resulted alcohol 67 undergo protection with MOM-Cl in the presence of DIPEA in CH2Cl2 to afford MOM ether which then deblocking of PMB with DDQ afforded 68 in good yield. Thus, it is clearly demonstrated that the two hydroxyl groups are differently protected and can be discriminated. Also interestingly both the ends of the carbon chain is decorated with different functional groups for convenient manipulationt. 13 Abstract In conclusion, the stereotetrad is a common substructure in polypropionate natural products. Four stereogenic centers next to each other result in eight possible diastereomeric combinations of this structure. Thus, an asymmetric synthesis of each of these combinations (anti, anti, anti; anti, anti, syn; anti, syn, anti; syn, anti, anti; syn, syn, anti; syn, anti, syn; anti, syn, syn and syn, syn, syn) demands accurate planning and careful realization in the laboratory. When the synthesis of a stereotetrad is a part of a total synthesis of a more complex molecule the situation becomes even more complicated. If the stereotetrad fragment can be cleaved retro synthetically into an independent sub-goal, its synthesis is often more straightforward than in the case where the stereochemistry of the stereotetrad is created by a linear approach. In the latter situation, the stereochemistry and structure of the remaining molecule has to be considered and it usually limits the possible strategies to a minimum. Chapter III: TosMIC mediated synthesis of Amides Section A: InCl3 catalyzed C-C coupling of aryl alcohols with TosMIC This section dealt with the synthesis of amides through InCl3 catalyzed carbon-carbon bond formation of aryl alcohols with TosMIC. To construct C-C bonds, coupling reactions between reactive nucleophiles such as organometallic compounds (R1M) and halides or a related species (RX) are undoubtedly a useful process. The species RX and R1M are often prepared from alcohols (ROH) and active methylenes (R1H), respectively. However, the coupling reaction intrinsically produces a salt (MX) alongside the desired product (R-R1). The direct reaction between ROH and R1H would be an ideal process for C-C bond formation because preparation of the reactive materials would not be required and only H2O would be generated as a side product. This process would significantly save energy during multistep transformations and separation of the product from the salt. Thus, a catalyst for the reaction is required that activates either ROH or R1H and has low oxophilicity and insensitivity to water. 14 Abstract Catalytic activation of alcohols is generally difficult because of the inefficient leaving-group ability of the hydroxyl group. On the otherhand p-toluenesulfonylmethyl isocyanide38 TosMIC a versatile, widely applicable reagent that constitutes a densely funC-nucleosides (Ref. 49b) R' R O R Tos 'R NC OH R 'R C N Passerini (Ref. 49d, 49f) S O O TosMIC Figure 6 ctionalized building block bearing an active methylene group. a Lewis acid mediated direct C-C coupling was envisaged between TosMIC and aryl alcohols which would result in α-alkylated TosMIC as products (Figure 6),39 however an N-substituted amide was obtained instead (Scheme 7). To the best of our knowledge, this is the first report on the use of isonitrile in such a mechanistic pathway.40 OH + TosMIC R' 78 69-77 R = R1 = alkyl, aryl, heteroaryl etc R O NH InCl3 (5 mol%) o CH3CN, 80 C R R' 79-87 Tos + R R' O 'R R by product Scheme 7 Accordingly the coupling reaction was performed between, benzhydrol 69 and TosMIC 78 in the presence of FeCl3 (5 mol%) at 80 oC in acetonitrile as solvent to afford amide 79 in 73% yield along with the corresponding dimeric ether (9%) as a byproduct. In order to minimize byproduct formation, different Lewis acids such as BF3.OEt2, ZrCl4, Sc(OTf)3 and InCl3 were screened under similar reaction conditions to afford 79 and the dimeric ether in varying yields. It was found that when the reaction was carried out using InCl3 as the catalyst the amide 79 (92%) was formed in a shorter reaction time. Amide 79 was identified from its 1H NMR spectral data. Further the versatility of the methodology was studied with various substrates. Thus, alcohols 70-77, including an α,β-unsaturated alcohol 70, a tertiary alcohol 72, bicyclic benzylalcohol 73, and heteroaryl benzylalcohol 74 afforded the corresponding amides 80-87 under standard reaction conditions in good to high yields (75-88%) (Table 3). 15 Abstract In conclusion, we have reported a new InCl3 mediated C-C coupling reaction between aryl alcohols and TosMIC to afford the corresponding amides in good to high yields. This reaction besides being atom economical in nature is also a novel protocol that paves way for further exploitation of TosMIC. Table 3 Coupling reaction between various alcohols and TosMIC under optimized conditions Entry Productb Alcohol OH 1 Ph Yield (%)c 79 2 92 80 4 87 81 8 76 82 4 85 83 3 88 84 4 80 85 4 76 86 3 78 87 6 75 Ph 69 2 Time [h] OH Ph Ph 70 OH 3 Ph CH3 71 OH 4 Ph 72 Ph CH 3 OH 5 73 OH 6 S 74 Ph OH Ph 7 HO 75 OH Ph 8 76 9 OH 77 Section B: Indium mediated synthesis of -keto-(E)-enamino esters through C-H activation of 1,3-dicarbonyl compounds This section dealt with the Synthesis of -keto-(E)-enamino esters through InCl3 catalyzed carbon-carbon bond formation of 1,3-dicarbonyl compounds with TosMIC. 16 Abstract Enamination of -dicarbonylcompounds forming β-enamino ketones and esters, is an important and widely used transformation.41 The latter compounds are highly versatile class of intermediates for the synthesis of heterocycles and biologically active compounds.42 In particular, the enamino ketone moiety has attracted much interest because it is a basic and versatile structure for the synthesis of natural therapeutic and biologically active analogues including taxo,43 anticonvulsivant,44 anti-inflammatory,45 and antitumor agents,46 as well as quinolone antibacterials47 and quinoline antimalarials and also such as β-enamino acids, -enamino alcohols or β-enamino esters.48 Because of this usefulness and in continuation of our effort to expand the utility of p-toluenesulfonylmethyl isocyanide (TosMIC) as an isonitrile component49 we intended to develop a novel protocol of accessing -keto-(E)-enamino esters by considering the fact that 1, 3-dicarbonyl compound(s) can be activated by the Lewis acids50 and the ensuing enolate could be trapped, in situ, with TosMIC as a worthwhile proposition (Scheme 8). Tos O R1 O O R2 + TosMIC InCl3 CH3CN, 80 0C 78 R1 = CH3, Cl-CH2, 4-NO2-Ph etc R2 = CH3, OEt R1 NH O R2 Scheme 8 Accordingly, we first screened various commercially available isonitriles such as tert-butyl isocyanide, cyclohexyl isocyanide and TosMIC 78 with ethyl acetoacetate 88 in the presence of InCl3 (5 mol%) as the Lewis acid catalyst in acetonitrile as a solvent at 80 C in a bid to access the respective -keto-(E)-enamino ester. Gratifyingly, TosMIC was o the only isonitrile to have reacted under the said reaction conditions to afford -keto-(E)enamino esters 95 (91%) mainly due to the multiple reactivity of TosMIC that emerges from it’s densely functionalization while the other isonitriles were inactive. Also we screened several Lewis acids, namely FeCl3 (20%), BF3.OEt2 (15%) and ZrCl4 (30%) for the same transformation but found InCl3 the best yielding. This behavior maybe attributed to the fast decomposition of TosMIC. 17 Abstract Table 4 C-C Coupling between carbonyl compound and TosMIC under optimized conditionsa Entry Productb Carbonyl compd. Time [h] O O 1 H3C O H3C O OEt HN 95 CH2Tos OEt 88 O 2 96 89 O 3 O H3C O O 91 O H3C R OEt OBn HN CH2Tos 92 O 94 6 82 O H3C OBn 6 4 HN 98 CH2Tos O OEt 86 OEt R = 4-NO2 O 10 O OEt R R = 4-NO2 5 CH3 HN 97 CH2Tos 90 4 88 O H3C CH3 O 5 HN CH2Tos OEt O 91 OEt O Cl 3 O Cl O Yield (%)c 99 O EtO no reaction OEt 93 O 7 H3C H3C H N O Tos OEt CN CH3 94 Tos 100 -keto-(E)-enamino ester 91 was identified from its 1H NMR spectrum, 13C NMR spectrum, IR spectrum revealed the characteristic peaks and stretching frequencies 18 Abstract respectively, ofcourse, ESIMS spectrum show the corresponding product. On the otherhand, the geometry was unambiguously proved experimentally by 1D nOe study of -keto-(E)-enamino ester 95, which reveals the characteristic olefin proton was in cis position to ester, as well as amine derivative was in trans to ester due to correlation of O O H3C CH3 H O HN H CH2 Tos Figure 7 olefin proton with methylene of ester group has been observed (Figure 7). Further it was supported by HB values of eanaminones and enamino esters studied independently from 17 O NMR.51Accordingy, formation of the compound showed in structure B has been believed strongly because it is well known that ester carbonyl groups are less basic than O OEt H3C CH3 O O H A O H N CH2Tos OEt N CH2Tos B Figure 8 ketone carbonyls, and consequently ester carbonyls are expected to be poorer hydrogen bond acceptors than ketone carbonyls (Figure 8). Subsequently, in an effort to generalize the synthetic methodology, we studied various 1,3-dicarbonyl compounds, 89-92, possessing different functional groups and substituents (Table 4), including the -chiral 1,3-dicarbonyl compound 92 under the standardized reaction conditions to afford corresponding β-keto-(E)-enamino esters 96-99 in good yields except in the case of di ketone 90, where the product obtained is β-keto enaminone 97 (Table 4). Similarly there was determined no such product of desired and un desired new prodct 100 in the case of ethyl malonate 93 with TosMIC 78. Interestingly, self coupling of TosMIC to result undesired new product 100 (Scheme 9) has been observed first time during the reaction between 94 with TosMIC 78 19 Abstract because of unsuitable di ketone system, but it could be act as chelating ligand52 in the presence of InCl3 to afford undesired new compound 100. H N 94 TosMIC 78 InCl3, CH3CN CN Tos Tos 100 Scheme 9 In conclusion, we have reported a new protocol for the synthesis of -keto-(E)enamino esters and -keto enaminone in good yields by the C-C coupling between 1,3dicarbonyl compounds and TosMIC via Lewis acid catalyzed enolization pathway. 20