Chapter Chapter Reactions of 3-hydroxy-2-pyrone 11 Chapter 2.1 3-Hydroxy-2-pyrone 3-Hydroxy-2-pyrone is a compound that can be synthesized from the pyrolysis of mucic acid in the presence of potassium dihydrogen phosphate and phosphorous pentoxide (Scheme 2.1).1 A mixture of products is obtained and by tuning the pH of the mixture carefully, extraction can be done to singly extract the pyrone as a clean product that is suitable for carrying out reactions. Ether is used as a solvent to extract the product into the organic phase using a continuous extraction process. Scheme 2.1 Synthesis of from mucic acid. Corey et al. had used as a vinylketene equivalent that reacted like a diene in the Diels-Alder process (Figure 2.1).2 Figure 2.1 3-Hydroxy-2-pyrone and vinylketene. Under high temperature conditions, DA reactions can proceed smoothly followed by decarboxylation reaction to remove CO2. In this way, the synthesis of a variety of 12 Chapter dihydrophenolic compounds was realized. In the report, thermal conditions were required for the reactions to take place. The dihydrophenolic products obtained contained one chiral centre (Scheme 2.2). The asymmetric version was not evaluated in the communication. OH O + O OH CO2Me CO2Me CO2Me benzene 73% yield 115oC, 40hr CO2Me OH CO2Me CO2Me toluene 56% yield o 170 C, 22hr OH CO2Me toluene 200oC, 22hr CO2Me 50% yield Me Scheme 2.2 Reactions of and activated olefins under reflux conditions to give dihydrophenolic compounds. Scheme 2.3 Reaction of and 1,4-naphthoquinone. Tsuboi’s group also used to react with 1,4-naphthoquinone in refluxing PhMe in the presence of NEt3 (Scheme 2.3).3 A Diels-Alder reaction is likely to be the first step followed by the decarboxylation reaction under high temperature conditions. This is 13 Chapter similar to the previous route reported by Corey (Scheme 2.2) except that a base (NEt3) is used to facilitate the DA reaction. This reaction provided access to anthraquinone derivatives. Scheme 2.4 Reaction of with chiral acrylates and its synthesis leading to (-)-eutipoxide. The base-catalyzed DA reaction of was also extended to the use of a chiral acrylate as a dienophile (Scheme 2.4).4 The chiral 2-oxazolidinone moiety was responsible for inducing the asymmetry in the bicycloadduct. The product was obtained in >70% yield. The chiral auxiliary could be transformed to a methyl ester group by MeONa/MeOH. Subsequently, several steps were carried out successfully to yield the final product. By switching the chiral centre on the 2-oxazolidinone group, the synthesis of (+)-eutipoxide could also be achieved. 14 Chapter 2.2 2-Pyrones and derivatives The majority of 2-pyrone reactions lies in its use as a diene in DA reactions. was mentioned in the earlier part (Section 2.1) and that a small amount of base is usually sufficient to catalyze its DA reaction with other dienophiles. This is an added advantage as this provides a pathway whereby milder conditions can be used for the DA reactions. However, a large part of 2-pyrone chemistry also involves compounds that contain no hydroxyl group at the 3-position. To-date, much of the DA reactions of 2-pyrones (no hydroxyl group at 3-position) require either high temperature or pressure for them to work. There are no reports that demonstrate that a base is capable of catalyzing DA reactions of such 2-pyrones. On the other hand, the products they produce are significantly useful in the course of synthetic organic chemistry. It is thus worthwhile to study these reactions and understand their mechanisms and to develop milder methods to carry them out. Scheme 2.5 Reaction of 2-pyrone with vinyl acrylate in a consecutive Diels-Alder reaction. MarkÓ et. al performed a consecutive DA reaction using just the 2-pyrone and a vinyl acrylate in a one-pot procedure (Scheme 2.5).5 The conditions for the first DA required a high pressure of 19kbar delivering a good yield of 95%. The high pressure will 15 Chapter not affect the overall molecular structure. Subsequently, refluxing the product at a high temperature of 200oC promotes the decarboxylation reaction removing a molecule of CO2 giving a dihydrobenzene core. With the presence of a diene and an olefin in the same molecule, an intramolecular DA reaction took place to yield the tricyclic compound as shown. The hydroxyl group of was protected with a Me group and used as a diene.1 In this case, a base might not be able to catalyze a DA reaction as there is no hydroxyl group. It was reacted with acetylene dicarboxylate under reflux conditions (Scheme 2.6). Decarboxylation took place thereafter and an aromatic ring was formed. Like the example shown earlier (Scheme 2.3), this is also a route to attain phenols and its derivatives. Scheme 2.6 Reaction of 3-methoxy-2-pyrone and acetylene type dienophiles under reflux conditions. Posner and coworkers have also shown that the presence of a bromine atom at the 3- or 5- position can increase the reactivity of 2-pyrones.6-8 In a sealed vessel using CH2Cl2 as the solvent, 3-bromo-2-pyrone was reacted with electron-deficient olefins to give the normal electron demand DA products (Scheme 2.7). Applying the same conditions, it was also demonstrated that it can take part in inverse electron demand DA 16 Chapter reactions (with ether type olefins) to give DA products as well. The unique ambiphilic characteristic is not commonly found in a single diene but it is well embodied in this 2pyrone molecule. On the other hand, 5-bromo-2-pyrone was found to give cycloadducts slowly under thermal conditions with both electron-poor and electron-rich Scheme 2.7 Reaction of 3-bromo-2-pyrone and various dienophiles. O O + R 25-100oC, 2-5d 83-100% Br O R O Br R = CN, COMe, CO2H, OSiMePh2, p-Br-C6H4 Scheme 2.8 Reaction of 5-bromo-2-pyrone and various dienophiles. dienophiles. Despite the slow reaction rate, the bromo group at the 5-position has increased the diene reactivity as a high reaction temperature is no longer required (Scheme 2.8). Milder conditions can equally be applied for a reaction to take place. 17 Chapter Posner also reported commercially available silica gel as another inexpensive promoter for the DA reaction of the optically active pyrone lactate ester and benzyl vinyl ether (Scheme 2.9).9 The diastereoselectivity was 58% and the yield was 60% when it was carried out in toluene at -30oC. Me O O O CO2Me O O + O Bn SiO2, -30oC PhMe 60% yield d.e. 58% CO2Me O OBn O O Me H Scheme 2.9 Reaction of optically active pyrone lactate ester with benzyl vinyl ether using silica gel as a promoter. Scheme 2.10 Reaction of 3-carbomethoxy-2-pyrone with vinyl ethers in the presence of lanthanide shift reagents. This is another example that showed 2-pyrones can take part in inverse electron demand DA reactions. 3-Carbomethoxy-2-pyrone can react with vinyl ethers to give DA products in the presence of lanthanide shift reagents (Scheme 2.10).10 The authors reported that the use of strong Lewis acids can destroy the cycloadducts by gearing the products towards decarboxylation. Strangely, Yb(OTf)3 alone does not act as the catalyst 18 Chapter but the addition of (R)-BINOL generates a new active catalyst that promotes the reactions with moderate to good enantiomeric excess. Corey also utilized a pyrone in the synthesis of the sesquiterpene (±)-occidentalol (Scheme 2.11).11 The initial step involved reacting the pyrone with 4-methyl-3cyclohexenone at 150oC under nitrogen for 24h. Decarboxylation occurred under the reflux conditions to yield the basic decalin structure which upon further reactions gave the racemic alcohol. The yield of the DA product was about 25-40%. Further transformations led to the racemic product (±)-occidentalol. O O O Me O CO2Me + O 150oC 24h - not detected in reaction mixture - decarboxylation occured under reflux conditions MeO2C O Me OH Me (±)-occidentalol several steps Me O CO2Me Scheme 2.11 Corey’s synthesis of (±)-occidentalol from 3-carbomethoxy-2-pyrone. Previous examples had made used of either 3- or 5- substituted 2-pyrones for reactions. However, Cho and coworkers had shown that even 3,5-disubstituted 2-pyrone can be utilized for DA reaction (Scheme 2.12).12 The yield for the cycloadduct was acceptable and the product was used in the synthesis of (±)-joubertinamine. 19 Chapter Scheme 2.12 Reaction of 3-aryl-5-bromo-2-pyrone with vinyl thioether. Although has a structure that has a few functional groups (hydroxyl group, diene group and ester group), the major study lies in its use as a dienophile in Diels-Alder reactions. Its structural similarity to 4-hydroxy coumarin and its existence as a readily available enolate equivalent could have prompted its use as a donor in Michael or Aldol type reactions. OH a possible point of attack (alpha-attack) OH O O 3-hydroxy-2-pyrone O O point of attack for Michael reaction 4-hydroxycoumarin OH another point of attack (gamma-attack) O O Figure 2.2 Comparing various points of attack (as a Michael donor) in 3-hydroxy-2pyrone and 4-hydroxycoumarin. There are possible sites of attack in 3-hydroxy-2-pyrone which are namely the alpha site and the gamma site with respect to the alcohol (Figure 2.2). Deng reported that can react with α,β-unsaturated ketones to give Michael products.13 The products were 20 Chapter Table 2.1 Screening of catalysts and solvents for the Diels Alder reaction of and Nsubstituted maleimides. a Entry CPS Solvent R Temp/oC Yield/%a ee/%b 3a CH2Cl2 Ph rt 90 65(2) 3b CH2Cl2 Ph rt 85 32(0) 3c CH2Cl2 Ph rt 88 11(7) 3d CH2Cl2 Ph rt 91 40(0) 3a PhMe Ph rt 92 50(5) 3a THF Ph rt 86 26(0) 3a CHCl3 Ph rt 82 33(9) 3a Et2O Ph rt 80 45(0) 3a MeOH Ph rt 81 3(0) 10 3a MeCN Ph rt 82 5(0) 11 3a CH2Cl2 Ph -20 80 81(20) 12 3a CH2Cl2 Ph -40 82 85(15) 13 3a CH2Cl2 Ph -40 81 88(28) 14 3a CH2Cl2 Cy -40 82 88(20) 15 3a CH2Cl2 Bn -40 83 87(20) Isolated yield. b Chiral HPLC. 26 Chapter enantioselectivity drastically (Table 2.1, entries & 10). The best results were obtained when CH2Cl2 was used as the solvent. Other N-substituted maleimides were synthesised and they gave similar enantiomeric excess (Table 2.1, entries 14 & 15). The best result was obtained when the benzyl catalyst 3a was used. By lowering the temperature, the enantiomeric excess could be improved as can be seen from entries 11-15. This particular reaction is unique because the major isomer produced is the exo isomer compared to most other reports where endo product is the major isomer. O O + O OH O O N O O 10 mol% 3b CH2Cl2, rt 72h O HO N O 70% yield 70% ee O Scheme 2.18 DA reaction of and terminal olefin catalyzed by 3b. To demonstrate that the system is not limited to cyclic dienophiles, a terminal olefin was also used in the DA reaction with (Scheme 2.18). A slower reaction rate was observed but a steady conversion of the product was obtained. The enantiomeric excess was about 70%. However, the reaction rate was rather slow (72h) such that optimization of the reaction condition by lowering the temperature was not carried out. 27 Chapter Scheme 2.19 DA reaction of and 2d. The amino indanol which was developed for the asymmetric DA reactions of Nsulfonyl-3-hydroxy-2-pyridone (more about this reaction would be discussed in the next chapter), was also found to be a suitable catalyst for the Diels-Alder reaction of 3hydroxy-2-pyrone and N-mesityl maleimide (Scheme 2.19). The yield was about 95% with an endo:exo ratio of about 3:1. The major product had a higher enantioselectivity of 90%. With this, it was demonstrated that several catalysts developed in our lab were able to catalyze the reaction of 3-hydroxy-2-pyrone and various dienophiles giving moderate to high enantioselectivities. The enantiomer of product 5a was also used in the synthesis of the key intermediate of an SP antagonist RPR107880 (Figure 2.5).20 Substance P (SP) is a small peptide classified in the tachykinine family and it behaves like a neurotransmitter. The protecting group used in this synthesis was benzyl instead of the mesityl (2,4,6-C6H2) group. In this report, the authors used quinine as the catalyst and the best enantiomeric excess obtained for the cycloadduct was 63%. The method they used for obtaining the optically pure product was by recrystallization of the cycloadduct. 28 Chapter O O multi-step transformation N Bn O OH N Bn OMe O Diels-Alder product from 3-hydroxy-2-pyrone and N-benzyl maleimide O intermediate transformations N OH OMe O RPR 107880 Figure 2.5 DA product of and N-benzyl maleimide leading to the synthesis of RPR 107880. 29 Chapter 2.5 Vinylogous Aldol Reaction (VAR) of 3-hydroxy-2-pyrone 3-Hydroxy-2-pyrone is known to take part in Diels-Alder reactions with dienophiles.21 In an attempt to develop hetero-Diels-Alder reactions using 3-hydroxy-2-pyrone as a diene and aromatic aldehydes as dienophiles, it was discovered that a vinylogous aldol reaction takes place instead. Scheme 2.20 Investigation of with aldehydes to yield hetero-DA product. VAR is a powerful bond-forming reaction and has been adopted in the synthesis of several natural products.22 There are several examples whereby Lewis bases and Lewis acids are utilised as catalysts or promoters in VARs.23 However, the employment of a Bronsted base as a catalyst is rarer. In a VAR, there are two possible positions of attack, namely the α-addition and the γaddition (Scheme 2.21).24 The ratio of products formed is dependent on the type of dienolate and the reaction conditions.25 As such, there is a need to examine the reasons of attack at each position, as well as to optimize the reaction conditions in order to obtain the desired aldol product. 30 Chapter O O O OH O alpha-addition + Ar Ar H O OH OH Ar gamma-addition OH O O OH Scheme 2.21 Alpha and gamma attacks of pyrone on the aldehyde. Preliminary work for the type of base and the catalyst loadings were carried out using 3hydroxy-2-pyrone with 4-cyanobenzaldehyde (Table 2.2). When the reaction was first carried out with 10 mol% triethylamine (TEA), the reaction was very slow and failed to complete after days. Even when the catalyst loading was increased to 50 mol%, the reaction took 18 hours to complete. The reaction rate for methylpyrrolidine was similar to that of TEA. This was probably due to the fact these two BrØnsted bases are both tertiary amines and have similar pKa values. One important observation is that pyrrolidine, a secondary amine does not catalyze the reaction. This indicated that the VAR likely does not proceed via an enamine intermediate. Figure 2.6 Organic bases used for VAR 31 Chapter Table 2.2 Reaction between and 4-cyanobenzaldehyde using different catalysts. Entry Base Loading/% Time/hr Conversion/%a TEA 10 96 80 TEA 50 18 95 TBD 10 48 95 TBD 15 30 95 TBD 30 12 95 Pyrrolidine 15 96 trace N-methyl pyrrolidine 15 96 90 All entries employed eq. of 1, eq. of 4-cyano benzaldehyde and 0.5 ml of solvent. a Conversion determined using 1H NMR of crude reaction mixture. The reaction was greatly improved when 1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD) was employed as the catalyst in the reaction.26 It has been shown that TBD is able to promote reactions such as the Wittig reaction,27 the Henry reaction28 and the addition of phosphites to carbonyl compounds28 and the addition of azoles to α,β –unsaturated nitriles and esters.29 The reaction with 10 mol% TBD achieved 95 % conversion within 48 hours. 32 Chapter A slight increase of catalyst loading to 15 mol% allowed a reasonable rate of completion in 30 hours. Though a higher catalyst loading of TBD further improved the reaction rate, 15 mol% was the loading of choice. The solvent screen was carried out and the general trend that more polar solvents gave a faster reaction rate was observed. Reaction in non-polar solvents such as toluene failed to complete after a long reaction time. When the reaction was carried out in chlorinated solvents (CH2Cl2, CHCl3 and 1,2-DCE) or THF, generally high conversions to the products were observed after about 48h of reaction. Using a polar protic solvent such as MeOH, the reaction rate was simliar to when CH2Cl2 was used as the solvent, reaching a conversion of 80% after two days. Carrying out the reaction in polar aprotic solvent such as MeCN took 19 hours to complete. The fastest reaction rates were obtained when polar aprotic solvents such as DMSO and DMF were used. The reactions took only 30 to complete. 33 Chapter Table 2.3 Reaction between and 4-cyanobenzaldehyde using different solvents. NC O OH O O OH + H catalytic base solvent, rt VAP NC O O OH Entry Solvent Time/hr Conversion PhMe 96 50 THF 48 99 CHCl3 48 95 CH2Cl2 48 80 (CH2Cl)2 30 95 MeCN 19 98 MeOH 48 80 DMF 0.5 99 DMSO 0.5 99 All entries employed eq. of 1, eq. of 4-cyano benzaldehyde, 0.15 eq. of TBD and 0.5 ml of solvent. 34 Chapter With optimized conditions, the VARs of 3-hydroxy-2-pyrone were attempted with different aldehydes. Aromatic aldehydes with various substituents were used, as well as aliphatic aldehydes. The most reactive aldehydes were the electron deficient aldehydes, giving the fastest rates of reaction and relatively good yields of the aldol adducts. This was expected as electron-withdrawing substituents can activate the carbonyl carbon towards attack by a nucleophile. The VARs with para-halogenated benzaldehydes worked well, even though halogens not demonstrate a strong electron withdrawing effect. All these reactions completed within 18 hours and gave relatively good yields. Only the gamma addition adducts were observed. The VAR with aromatic aldehyde with an electron donating group could work well too as in the case of 4-methylbenzaldehyde (Table 2.4, entry 6). However, as electron donating substituents deactivate the carbonyl carbon towards nucleophilic addition, it was of no surprise that this aldehyde is less reactive. The reaction proceeded slowly and did not complete. A yield of 46% was obtained after 48 hours. An aliphatic aldehyde initially tested (acetaldehyde) is a liquid with a low boiling point (b.p. 20oC). It was difficult to assess if the aldehyde evaporated when used in small amounts. When i-butyl aldehyde was used for the VAR, a slower reaction rate was observed (conditions applied were those when aromatic aldehydes were used). As such, the 35 Chapter Table 2.4 Reaction between and various aldehydes. Solvent TBD/mol% Time/h VAP, Yield/%a DMSO 15 0.5 VAP 1, 82 DMSO 15 0.5 VAP 2, 75 DMSO 15 0.5 VAP 3, 80 DMSO 15 24 VAP 4, 51b DMSO 15 18 VAP 5, 84 DMSO 15 48 VAP 6, 46 Neat 30 48 VAP 7, 80 DMSO 15 24 VAP 8, 82 DMSO 15 24 VAP 9, 75 Entry Substrate S a Isolated yield after flash column chromatography. b Combined yields of alpha and gamma attack products. 36 Chapter VAR was carried out under neat conditions. Due to the lower reactivity of the aldehyde, a larger amount of TBD was required. The yield obtained was relatively good and only the gamma product was obtained. This demonstrated that this reaction is not restricted to only aromatic aldehydes. On the other hand, other carbonyls such as ketones were also evaluated as suitable partners for VAR reactions with 3-hydroxy-2-pyrone (Figure 2.7). So far, the VAR of 3hydroxy-2-pyrone could be carried out with aldehydes and not with ketones. There was no reaction even with ketones that contain electron withdrawing substituents. 3-hydroxy-2pyrone also did not react with certain aldehydes such as 5-methyl furfuraldehyde and pyrrolecarboxaldehyde. Figure 2.7 Ketones used. The structure of the VAR product was also confirmed by X-ray crystallography. The VAR product of 3-hydroxy-2-pyrone and 2-chloro-5-nitrobenzaldehyde was protected with TsCl in the presence of triethylamine using standard procedures. Scheme 2.22 Protection of one hydroxy group of VAP with a tosyl group. 37 Chapter Figure 2.8 Crystal structure of VAP 10. The crystal structure of VAP 10 indicated a γ-attack of the pyrone on the aldehyde (Figure 2.8). It has been shown that 3-hydroxy-2-pyrone reacts in a vinylogous aldol reaction with aldehydes, catalyzed by a BrØnsted base, to give γ addition products. This VAR can be used for most aromatic aldehydes using DMSO as solvent. This VAR can also take place with aliphatic aldehydes under neat conditions. Research is ongoing to extend this vinylogous aldol reaction to an enantioselective version with the use of suitable chiral bases. In conclusion, we have described the various catalysts that could catalyze the DielsAlder reactions of 3-hydroxy-2-pyrone with mostly, N-substituted maleimides, to form bicyclic products. 2-Pyrones (without the hydroxy group) were also reviewed to be excellent dienes in Diels-Alder reactions as they provide access to several synthetically useful intermediates in organic synthesis. The challenge still exists for organic chemists to 38 Chapter explore and develop the catalytic asymmetric versions. was also unexpectedly found to form a vinylogous aldol product with aldehydes, although no hetero Diels-Alder reactions took place. As this finding still lies in its infant stage, the scope and variants in the reaction remains to be looked into. 39 Chapter References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. Profitt, J. A.; Jones, T.; Watt, D. S. Synth. Commun. 1975, 5, 457-460. Corey, E. J.; Kozikowski, A. P. Tetrahedron Lett. 1975, 28, 2389-2392. Komiyama, T.; Takaguchi, Y.; Tsuboi, S. Synlett 2006, 1, 124-126. Shimizu, H.; Okamura, H.; Iwagawa, T.; Nakatani, M. Tetrahedron 2001, 57, 19031908. (a) Swarbrick, T. M.; Marko, I. E.; Kennard, L. Tetrahedron Lett. 1991, 32, 25492552. (b) Marko, I. E.; Seres, P.; Swarbrick, T. M.; Staton, I.; Adams, H. Tetrahedron Lett. 1992, 33, 5649-5652. Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Afarinkia, K. Tetrahedron Lett. 1991, 32 (39), 5295-5298. Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Johnson, N. J. Org. Chem. 1992, 57 (15), 4083-4088. Afarinkia, K.; Posner, G. H. Tetrahedron Lett. 1992, 33 (51), 7839-7842. Posner, G. H.; Carry, J. C.; Lee, J. K.; Bull, D. S.; Dai, H. Y. Tetrahedron Lett. 1994, 35 (9), 1321-1324. (a) Marko I. E. and Evans G. R. Synlett 1994, 431 (b) Marko I. E., Evans G. R., Declercq J.-P., Feneau-Dupont J. and Tinant B. Bull. Soc. Chim. Belg. 1994, 103, 295. Watt D.; Corey E.J. Tetrahedron Lett. 1972, 4651. Tam, N. T.; Cho, C. G. Org. Lett. 2007, (17), 3391-3392. Wang, Y.; Li, H. M.; Wang, Y. Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am.Chem. Soc. 2007, 129 (20), 6364-6365. Halland, N.; Hansen, T.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2003, 42 (40), 4955-4957. (a) Komiyama, T.; Takaguchi, Y.; Tsuboi, S. Tetrahedron Lett. 2004, 45 (33), 6299-6301. (b) Komiyama, T.; Takaguchi, Y.; Gubaidullin, A. T.; Mamedov, V. A.; Litvinov, I. A.; Tsuboi, S. Tetrahedron 2005, 61 (9), 2541-2547. For a recent review on application of compounds containing the bis-oxazoline moiety, see: Hargaden, G. C.; Guiry, P. J. Chem. Rev. 2009, 109 (6), 2505-2550. Akalay, D.; Durner, G.; Gobel, M. W. Eur. J. Org. Chem. 2008, 14, 2365-2368. (a) Leow, D. S.; Lin, S. S.; Chittimalla, S. K.; Fu, X.; Tan, C. H. Angew. Chem. Int. Ed. 2008, 47 (30), 5641-5645. (b) Jiang, Z. Y.; Pan, Y. H.; Zhao, Y. J.; Ma, T.; Lee, R.; Yang, Y. Y.; Huang, K. W.; Wong, M. W.; Tan, C. H. Angew. Chem. Int. Ed. 2009, 48 (20), 3627-3631. Xu, J. Y.; Fu, X.; Low, R. J.; Goh, Y. P.; Jiang, Z. Y.; Tan, C. H. Chem. Commun. 2008, 43, 5526-5528. Okamura, H.; Shimizu, H.; Nakamura, Y.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 2000, 41 (21), 4147-4150. (a) Okamura, H.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 1995, 36, 5939. (b) Okamura, H.; Morishige, K.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 1998, 39, 1211. 40 Chapter 22. 23. 24. 25. 26. 27. 28. 29. For a review on the vinylogous aldol reaction and its application in natural product synthesis, see: Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929. For examples, see: (a) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360. (b) Denmark, S. E. J. Am. Chem. Soc. 2003, 125, 7800. (c) Denmark, S. E.; Heemstra, J. R. Jr. J. Am. Chem. Soc. 2006, 128, 1038. (d) Palombi, L.; Acocella, M. R.; Celenta, N.; Massa, A.; Villano, R.; Scettri, A. Tetrahedron: Asymmetry, 2006, 17, 3300. (e) Bluet, G.; Campagne, J.-M. Tetrahedron Lett. 1999, 40, 5507. For a review on the catalytic enantioselective vinylogous aldol reaction, see: Denmark, S. E.; Heemstra, J. R. Jr.; Beutner, G. L. Angew. Chem. Int. Ed. 2005, 44, 4682. Rathke, M. W.; Sullivan, D. Tetrahedron Lett., 1972, 13, 4249. Our group had used TBD as a catalyst successfully in certain reactions, for examples, see: (a) Ye, W.; Xu, J.; Tan C-T., Tan, C-H. Tetrahedron Lett., 2005, 46, 6875. (b) Jiang, Z.; Zhang, Y.; Ye W. Tan, C-H. Tetrahedron Lett., 2007, 48, 51. Simoni, D.; Rossi, M.; Rondanin, R.; Mazzali, A.; Baruchello, R.; Malagutti, C.; Roberti, M.; Invidata, F. P. Org. Lett., 2000, 2, 3765. (b) Edwards, M. G.; Williams, J. M. J. Angew. Chem., Int. Ed. 2002, 41, 4740. Simoni, D.; Rondanin, R.; Morini, M.; Baruchello, R.; Invidiata, F. P. Tetrahedron Lett., 2000, 41, 1607. Horváth, A. Tetrahedron Lett., 1996, 37, 4423. 41 [...]... maleimides Entry Solvent R Temp/oC Yield/%a ee/%b 1 3a CH2Cl2 Ph rt 90 65 (2) 2 3b CH2Cl2 Ph rt 85 32 (0) 3 3c CH2Cl2 Ph rt 88 11(7) 4 3d CH2Cl2 Ph rt 91 40(0) 5 3a PhMe Ph rt 92 50(5) 6 3a THF Ph rt 86 26 (0) 7 3a CHCl3 Ph rt 82 33 (9) 8 3a Et2O Ph rt 80 45(0) 9 3a MeOH Ph rt 81 3( 0) 10 3a MeCN Ph rt 82 5(0) 11 3a CH2Cl2 Ph -20 80 81 (20 ) 12 3a CH2Cl2 Ph -40 82 85(15) 13 3a CH2Cl2 Ph -40 81 88 (28 ) 14 3a CH2Cl2 Cy... Chapter 2 O O multi-step transformation N Bn O OH N Bn OMe O Diels-Alder product from 3- hydroxy- 2- pyrone and N- benzyl maleimide O intermediate transformations N OH OMe O RPR 107880 Figure 2. 5 DA product of 1 and N- benzyl maleimide leading to the synthesis of RPR 107880 29 Chapter 2 2.5 Vinylogous Aldol Reaction (VAR) of 3- hydroxy- 2- pyrone 3- Hydroxy- 2- pyrone is known to take part in Diels-Alder reactions. .. (cat.), acetone, rt, (71% yield, three steps), (v) DIBAL-H (1.5 eq.), Et2O, -78oC; (vi) t-BuOK, CHCl2CO2Me (1.0 eq.), THF, (71% yield, two steps) Scheme 2. 14 Synthesis leading to 4-halo -3- hydroxy- 2- pyrone 22 Chapter 2 2.4 Asymmetric reactions of 3- hydroxy- 2- pyrone Scheme 2. 15 DA reaction of 1 and 2c The reaction between 3- hydroxy- 2- pyrone and N- benzyl maleimide can be catalyzed by a small amount of base... obtained and the enantioselectivity of the product was more than 80% This route could successfully provide a route to the anti-coagulant Warfarin Recrystalliztion using acetone/water mixture could increase the enantiomeric excess of the Michael product to >95% Scheme 2. 13 Organocatalytic Michael reaction of 4-hydroxycoumarin and α,βunsaturated enone 21 Chapter 2 2 .3 Synthesis of 3- hydroxy- 2- pyrone derivatives... containing a tertiary amine and a hydrogen bond donor would be useful in the DA reactions of this class of dienes 24 Chapter 2 Chiral pyrrolindinyl sulfonamides (CPS) 3a-d contain a pyrrolidine group (hydrogenbond acceptor) and a sulfonamide group (hydrogen-bond donor) They can be easily synthesised from commercially available amino alcohols and they were shown to be effective promoters in the tandem... out 27 Chapter 2 Scheme 2. 19 DA reaction of 1 and 2d The amino indanol which was developed for the asymmetric DA reactions of Nsulfonyl -3- hydroxy- 2- pyridone (more about this reaction would be discussed in the next chapter), was also found to be a suitable catalyst for the Diels-Alder reaction of 3hydroxy- 2- pyrone and N- mesityl maleimide (Scheme 2. 19) The yield was about 95% with an endo:exo ratio of. .. reaction of cyclic allylic bromides and dithiomalonates promoted by CPS 3a-d Figure 2. 4 Structures of chiral pyrrolidinyl sulphonamides (CPS) 3a-d The DA reaction completed in most common solvents such as CH2Cl2 and THF Polar solvents such as methanol and acetonitrile were found to decrease the 25 Chapter 2 Table 2. 1 Screening of catalysts and solvents for the Diels Alder reaction of 1 and Nsubstituted... 33 Chapter 2 Table 2 .3 Reaction between 1 and 4-cyanobenzaldehyde using different solvents NC O OH O O OH 1 + H catalytic base solvent, rt VAP 1 NC O O OH Entry Solvent Time/hr Conversion 1 PhMe 96 50 2 THF 48 99 3 CHCl3 48 95 4 CH2Cl2 48 80 5 (CH2Cl )2 30 95 6 MeCN 19 98 7 MeOH 48 80 8 DMF 0.5 99 9 DMSO 0.5 99 All entries employed 1 eq of 1, 4 eq of 4-cyano benzaldehyde, 0.15 eq of TBD and 0.5 ml of. .. Feneau-Dupont J and Tinant B Bull Soc Chim Belg 1994, 1 03, 29 5 Watt D.; Corey E.J Tetrahedron Lett 19 72, 4651 Tam, N T.; Cho, C G Org Lett 20 07, 9 (17), 33 91 -33 92 Wang, Y.; Li, H M.; Wang, Y Q.; Liu, Y.; Foxman, B M.; Deng, L J Am.Chem Soc 20 07, 129 (20 ), 636 4- 636 5 Halland, N. ; Hansen, T.; Jorgensen, K A Angew Chem Int Ed 20 03, 42 (40), 4955-4957 (a) Komiyama, T.; Takaguchi, Y.; Tsuboi, S Tetrahedron Lett 20 04,... 2. 15) Preliminary studies included the screening of the following oxazoline-containing compounds as catalysts for the reactions (Figure 2 .3) These bis-oxazolines (BOX) are commonly used for metal-catalyzed reactions and had their roles as ligands binding to the metal centre.16 To the best of our knowledge, there was only one report describing that these ligands could catalyze the DA reactions of anthrones . 4-halo -3- hydroxy- 2- pyrone. Chapter 2 23 2. 4 Asymmetric reactions of 3- hydroxy- 2- pyrone Scheme 2. 15 DA reaction of 1 and 2c. The reaction between 3- hydroxy- 2- pyrone and N- benzyl maleimide. Chapter 2 15 2. 2 2- Pyrones and derivatives The majority of 2- pyrone reactions lies in its use as a diene in DA reactions. 1 was mentioned in the earlier part (Section 2. 1) and that. Chapter 2 11 Chapter 2 Reactions of 3- hydroxy- 2- pyrone Chapter 2 12 2. 1 3- Hydroxy- 2- pyrone 3- Hydroxy- 2- pyrone 1 is a compound that can