Chapter Chapter Guanidine Catalyzed Enantioselective Desymmetrization of meso-Aziridines with Thiols 23 Chapter 2.1 Bicyclic guanidine catalyzed enantioselective desymmetrization of meso N-tosyl aziridines with thiols 2.1.1 Bicyclic guanidine catalyzed enantioselective reactions Guanidine derivatives (Figure 2.1) are widely utilized as strong bases in synthetic organic chemistry due to their high pKa values.1 Chiral guanidine derivatives function as asymmetric catalysts by exploiting the great basicity of guanidine group and the special hydrogen bonding pattern of the guanidinium ion. This research topic has increasingly attracted great interest and the asymmetric catalytic ability of chiral guanidine and guanidinium has been demonstrated in a large variety of reactions, such as Henry reaction2, Michael reaction3, Mannich reaction4, electrophilic amination5, Strecker reaction6, alkylation7, trimethylsilylcyanation8, nucleophilic epoxidation9, asymmetric silylation of secondary alcohols10, reduction of phenacyl bromide11, alkylative esterification12, azidation13, transamination14, Claisen rearrangement15. Figure 2.1 General structure of guanidine. Our group has reported an efficient synthetic route to afford a series of chiral bicyclic Brønsted-basic guanidines, from chiral aziridines, with overall yields of 43-71%.16 This synthetic route was modified from Corey’s work.6b Bicyclic chiral guanidine catalyst 39 was prepared according to the reported procedure as shown below (Scheme 2.1). N-Tosyl aziridine 35 was readily prepared from its corresponding 24 Chapter commercially available α-amino alcohol 34. Triamine unit 37 was easily obtained by treating 35 with NH3 bubbled into its MeOH solution. The nucleophilic attack occurred preferentially at the sterically least hindered carbon atom. The subsequent triamine 38 was prepared by using sodium in liquid ammonia to remove tosyl groups without further purification. The crude triamine 38 was then subjected to the final cyclization step, leading to the guanidinium salt 39·HI in 71% total yield from its amino alcohol. The guanidine catalyst 39 was obtained from filtration through K2CO3 column. Scheme 2.1 Synthesis of symmetrical chiral bicyclic guanidine 39.16 Chiral guanidine 39 was found to be an effective catalyst for asymmetric Michael reactions (Scheme 2.2).17 The initial investigation revealed that the additions of 1,3-diketone 41a and β-ketoester 41b to maleimide 40 provided the Michael adducts in high enantioselectivities and high yields. However, these reactions were slow and required 20 mol% of catalyst. The more reactive β-keto thioesters 41c-d and 25 Chapter dithiomalonates 41e-f were tested and the reaction rate was considerably enhanced. With guanidine 39 as the catalyst, adducts 42c-f were obtained in high yields and excellent ees with diastereomeric ratios of approximately 1:1 (42c-d). The catalyst loading of 39 can be decreased to mol% for substrate 41d. Scheme 2.2 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide with 1,3-diketones, β-ketoesters, dithiomalonates. 17 Thiomalonates were then employed as the donors for further investigation in an attempt to extend the acceptor scope of this reaction (Scheme 2.3). Cyclic enones 43a-b and furanone 43c afforded the Michael adducts 44a-c in high yields and excellent enantioselectivities. The reactions were typically faster as thioesters are 26 Chapter more acidic than their O-esters counterpart due to the poor overlap of their C(2p) and S(3p) orbitals. Scheme 2.3 Chiral bicyclic guanidine catalyzed Michael reactions of cyclic enones and furanone with dithiomalonate 41f. 17 It was found that trans-4-oxo-4-arylbut-2-enoates 45 were useful acyclic Michael acceptors (Scheme 2.4).17 In the presence of mol% of guanidine 39, dialkyl thiomalonate 41f reacted with 45 smoothly to give adducts 46 in high yields and high enantioselectivities. This was a highly regioselective reaction in which the addition only occurred at the β position of the enone moiety. Scheme 2.4 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl trans-4oxo-4-arylbut-2-enoates. 17 Our group also investigated the Michael reactions between cyclic enone 43a and other 1,3-dicarbonyl compounds catalyzed by guanidine 39.16,18 Sulfonamides and amines were added as additives to enhance the reaction rate. Amongst them, 27 Chapter triethylamine (Et3N) was found to be the best additive and it could be used as the solvent, resulting in a significant increase of reaction rate and enantioselectivity. Generally, the Michael adducts were obtained in excellent enantioselectivities and high yields (Scheme 2.5). This strategy was expanded to include maleimides as the Michael acceptors. Remarkably, the reaction of ethyl maleimide with benzoylacetate 41b was complete within five minutes in triethylamine (Scheme 2.6). It was about 1000 times faster than in toluene. We speculated that triethylamine might be involved in the stabilization of the enolate-guanidinium complex, thereby enhancing the reaction rate. Scheme 2.5 Chiral bicyclic guanidine catalyzed Michael reactions of 2-cyclopenten1-one with various 1,3-dicarbonyl compounds. 16,18 28 Chapter Scheme 2.6 Chiral bicyclic guanidine catalyzed Michael reactions of ethyl maleimide with benzoylacetate using triethylamine as solvent.16,18 Chiral bicyclic guanidine 39 was also found to be effective in catalyzing phospha-Michael reactions between nitroalkenes and phosphine oxides (Scheme 2.7).19 A series of diaryl phosphine oxides 48 were screened and the best one bore the 1-naphthyl group. Excellent enantioselectivities were generally obtained for various nitroalkenes with di-(1-naphthyl) phosphine oxide at -40 °C. The ee values of the crystalline products could be enhanced by recrystallization. It was postulated that the phosphine oxide was tautomerized to the unstable but reactive nucleophile in the presence of guanidine catalyst. Scheme 2.7 Chiral bicyclic guanidine catalyzed phospha-Michael additions of various diaryl phosphine oxides to conjugated aryl nitroalkenes.19 Our group also reported the protonation of 1-phthalimidoacrylate 50 with thiophenols using chiral guanidine 39 as the catalyst (Scheme 2.8).20 Excellent yields and ee values were obtained for a series of arenethiols. The substitution pattern at the phthalimido group did not affect the enantioselectivity. This reaction was not 29 Chapter restricted to aromatic thiols; excellent ee value could also be obtained with diphenylmethanethiol. Adducts obtained could be converted into useful analogues of amino acid cysteine. Scheme 2.8 Chiral bicyclic guanidine catalyzed protonation of 1-phthalimidoacrylate with thiophenols.20 The scope of the reaction was extended to cyclic imides 52 (Scheme 2.9). Some optimizations were carried out and it was concluded that the 2,6-positions of Nsubstituted-aryl itaconimides were crucial for high enantioselectivities. Excellent yields and ees were obtained when diaryl phosphine oxides 48 were used as donors. Scheme 2.9 Chiral bicyclic guanidine catalyzed protonation of itaconimides with diaryl phosphine oxides. 20 It was also found that bicyclic guanidine 39 could catalyze both the additions of phosphine oxide 54 and tert-butylthiol to N-(2-tert-butylphenyl)itaconimide 55, leading to the formation of axially chiral cyclic imides in high yields with 30 Chapter diastereomeric ratios of approximately 1:1. High ee values were observed for the anti diastereoisomers. Scheme 2.10 Chiral bicyclic guanidine catalyzed protonation of axially chiral N-(2tert-butylphenyl)itaconimide.20 Scheme 2.11 Chiral bicyclic guanidine catalyzed Michael reactions of dithranol 57.21 Bicyclic chiral guanidine 58 was prepared according to the similar procedures as 39.16 It was also found to be a good basic catalyst for enantioselective Michael 31 Chapter reactions of 1,8-hydroxy-9-anthrone 57 (Scheme 2.11).21 In the presence of 10 mol% of guanidine 58, the reactions were performed well with maleimides and other activated olefins as the Michael acceptors. Excellent enantioselectivities and regioselectivities were obtained in all examples. Our group also successfully exploited chiral guanidine 58 as the catalyst for Diels-Alder reactions between anthrones 61 and activated olefins (Scheme 2.12).21 High yields and enantioselectivities were obtained with various anthrones in combination with maleimides. In many examples, the ee values were more than 98%. Excellent regioselectivities were also observed when 1,5-dichloro-9-anthrone 61d and 4-(N-methylamino)-9-anthrone 61e were used as the dienes. However, prolonged reaction time or the treatment with base led to ring-opening products with significant racemization. Scheme 2.12 Chiral bicyclic guanidine catalyzed Diels-Alder reactions of anthrones.21 32 Chapter Table 2.5 Desymmetrization of meso N-acyl aziridines 21a, 12a with benzenethiol 63a catalyzed by chiral guanidine 79b.a product yield /%b ee /%c 80a 78 34 24a 95 44 entry aziridine a All reactions were performed with 0.02 mmol of aziridine, 0.04 mmol of thiol and 0.8 mL of ether. b Isolated yield. c Determined by chiral HPLC. Table 2.6 Desymmetrization of meso N-acyl aziridine 12a with various thiols catalyzed by chiral guanidine 79b.a entry 63 R product yield /%b ee /%c 63b 63c 63d 63e 4-BrC6H4 2,6-Me2C6H3 2,6-Cl2C6H3 (C6H4)2CH 81a 81b 81c 81d 92 92 93 n.d. 59 67 84 n.d. a All reactions were performed with 0.02 mmol of aziridine, 0.04 mmol of thiol and 0.8 mL of ether. b Isolated yield. c Determined by chiral HPLC. was observed when 2,6-dimethyl benzenethiol 63c was employed (entry 2). The enantiomeric excess was significantly increased to 84% when the methyl groups of 63c 42 Chapter were replaced with Cl atoms (entry 3). The absolute configuration of 81c was determined to be (1R,2R) by X-ray crystallographic ananlysis (Figure 2.4). Nevertheless, this reaction was restricted to aromatic thiols; there was no reaction for aliphatic thiol, such as diphenylmethanethiol 63e (entry 4). Figure 2.4 X-ray structure of 81c. Table 2.7 Effect of catalyst loading on the desymmetrization of meso N-acyl aziridine 12a with benzenethiol 63d.a entry x mol% time /h yield /%b ee /%c 3d 4d 2 20 24 24 40 93 93 92 92 89 91 92 92 a All reactions were performed with 0.02 mmol of aziridine, 0.04 mmol of thiol and 0.8 mL of ether. b Isolated yield. c Determined by chiral HPLC. d With 2.0 mL of ether. It was found that the enantioselectivity of the desymmetrization of meso N-acyl aziridine 12a with benzenethiol 63d could be further improved by decreasing the catalyst loading (Table 2.7). With mol% of chiral guanidine 79b, the reaction was 43 Chapter complete in 20 hours at -20 °C, affording 81c in 93% yield with 89% ee (entry 1). The ee value was increased to 91% when mol% of catalyst was employed (entry 2). Diluting the reaction concentration to 0.01 M slightly enhanced the enantioselectivity without a decrease of yield and reaction rate (entry 3). The catalytic loading could be reduced to mol%, and the same enantioselectivity (92% ee) was obtained, albeit longer reaction time was required (entry 4). 2.3.2 Highly enantioselective desymmetrization of meso N-acyl aziridines with thiols With the optimized conditions in hand, we next investigated the desymmetrization of a wide range of meso N-3,5-dinitrobenzoyl aziridines 12 with 2,6-dichloro benzenethiol 63d (Table 2.8). In general, high yields and enantioselectivities were produced from both cyclic and acyclic aziridines using 1-5 mol% of catalyst 79b. As shown in Table 2.8, in the case of aziridines derived from cyclohexane (entry 1) and cyclopentane (entry 3), the use of mol% of chiral guanidine 79b provided the desired products in excellent enantioselectivities and yields. The reaction of aziridine derived from cyclohexene with mol% of catalyst resulted in low conversion and enantioselectivity at -50 °C (entry 2). Increasing temperature to -20 °C led to the completion of reaction and a higher ee value. These results suggested that the reaction was under kinetic control and the two enantiomers showed different reaction rate accelerations at higher temperature. For the bulkier aziridine 12f-g, a slightly increased catalyst loading of mol% was necessary for the reaction to complete (entries 4-5). Guanidine 79b was also found to be effective in catalyzing the desymmetrization of acyclic meso-aziridines bearing aliphatic and aryl substituents (entries 6-7). Aziridine 44 Chapter Table 2.8 Desymmetrization of various meso N-3,5-dinitrobenzoyl aziridines 12 with benzenethiol 63d catalyzed by guanidine 79b.a product x mol% temp /°C time /h yield /%b ee /%c 81c -50 48 92 94 82a 2 -50 -20 72 48 89 93 84 90 82b 1 -50 -20 48 60 91 94 89 94 82c 5 -50 -50 -20 72 72 72 67 85 91 91 92 95 82d -20 72 90 90 82e -20 48 91 93 82f -20 -20 48 48 81 93 75 88 entry 12 (R=3,5-dinitrobenzoyl) a All reactions were performed with 0.05 mmol of aziridine, 0.1 mmol of thiol and mL of ether. b Isolated yield. c Determined by chiral HPLC. 45 Chapter 12h reacted smoothly with 2,6-dichloro benzenthiol 63d to afford the ring-opened product in 91% yield and 93% ee. mol% of catalyst was required to promote the reaction rate of meso-aziridine 12j, resulting in the formation of 82f in 93% yield and 88% ee. 2.3.3 Synthesis of chiral allylic amide Ring opening of aziridines has been widely applied in the synthesis of many highly functionalized nitrogen compounds.24 Our next focus was to achieve the synthetic utility of the enantiopure 1,2-difunctionalized products obtained. Herein, we selected 81c as a starting compound to synthesize cyclic allylic amide 84, which could be readily transformed into the corresponding cyclic allylic amine. Scheme 2.18 Preparation of chiral allylic amide 83. First, the ring-opened product 81c was easily oxidized to a sulfoxide intermediate 83 in high yield using meta-chloroperoxybenzoic acid (mCPBA) as the oxidant (Scheme 2.18). 83 was determined as a single diastereoisomer by 1H NMR studies. This 46 Chapter compound was subjected to pyrolysis25, affording the expected allylic amide 84 in moderate yield. The reaction was conducted at 120-130 °C in toluene. Different inorganic bases (e.g. Ca2CO3, Na2CO3, K2CO3 etc.) and organic bases (e.g. DBU) were tested under the reaction conditions, and K2CO3 provided the product in the best yield (60%) without any loss in optical activity. 2.3.4 Proposed mechanism Two plausible mechanisms for the nucleophilic ring opening: Scheme 2.19 Proposed catalytic cycle of chiral guanidine catalyzed desymmetrization of meso-aziridines. 47 Chapter The catalytic cycle of the chiral guanidine 79b catalyzed desymmetrization of meso-aziridines with benzenethiols was proposed as in Scheme 2.19. We reasoned that the guanidine group would deprotonate benzenethiol, generating an association in the guanidine-thiol complex 85. In the first step of the cycle, meso-aziridine 12a undergoes nucleophilic attack, leading to the formation of the ring-opened intermediate 86. Subsequently, compound 86 reacts with another molecule of benzenethiol to provide the product 81c and regenerate complex 85 to complete the catalytic cycle. Although the mechanism needs more evidences to support, the role of the chiral guanidine 79b as base could not be excluded in this reaction. Two plausible mechanisms could be envisaged for the origin of the enantioselectivity for the nucleophilic ring opening. In mechanism 1, aziridine 12a is attacked by the reactive nucleophile: guanidine-thiol complex 85. In mechanism 2, a guanidium-aziridine complex is formed through hydrogen bonding to the carbonyl functionality of the aziridine. Dissociation of phenylthiolate anion from guanidium cation is required in this mechanism. Further computational studies will be used to confirm the catalytic cycle and account for the stereochemistry of the products. 2.4 Guanidine catalyzed enantioselective desymmetrization of cisaziridine-2,3-dicaboxylates with thiols The nucleophilic ring opening of aziridine-2,3-dicarboxylate (Figure 2.5) is a direct synthetic approach towards β-substituted aspartates. Optically pure trans-aziridine-2,3dicarboxylates can be easily obtained from enzymatic resolutions.26 It has been shown that these compounds were highly reactive in the ring opening reactions with various nucleophiles.27 However, to the best of our knowledge, the asymmetric ring opening of cis-aziridine-2,3-dicarboxylates remains unexplored. Therefore, we aimed to develop a catalytic desymmetrization of cis-aziridine-2,3-dicarboxylates with thiols. 48 Chapter Figure 2.5 Structure of aziridine-2,3-dicarboxylate and aspartic acid. 2.4.1 Synthesis of cis-aziridine-2,3-dicarboxylates As shown in Scheme 2.20, cis-aziridine-2,3-dicarboxylate 91 was synthesized from aldehyde 87 in four steps. First, aldimine 88 was obtained in high yield by the condensation between diphenylmethyl amine and oxo-acetate 87. 88 was then subjected to a Brønsted acid (TfOH) catalyzed direct aza-darzens reaction, leading to the desired cis N-benzhydryl aziridine 89 as a single diastereoisomer in moderate yield.28 The subsequent removal of benzhydryl group was achieved by catalytic hydrogenation. Finally, the crude aziridine 90 was further easily converted into the corresponding activated aziridine 91 in the presence of carbobenzyloxy chloride (CbzCl) or 3,5-dinitrobenzoyl chloride with NaHCO3 as base, or tosyl chloride (TsCl) with pyridine as base.29 Scheme 2.20 Synthesis of cis-aziridine-2,3-dicarboxylates. 49 Chapter 2.4.2 Optimization studies on the enantioselective desymmetrization of cis-aziridine-2,3-dicaboxylates Table 2.9 Chiral guanidine 79a catalyzed desymmetrization of various cis-aziridine2,3-dicarboxylates 91a-d with benzenethiol 63a.a entry 5d 6d,e R PG time /h conversion /%b ee /%c Et Bu t Bu t Bu t Bu t Bu Cbz Cbz 3,5-dinitrobenzoyl Ts Ts Ts 24 72 18 18 24 24 100 90 100 100 100 100 28 55 51 68 72 cis-91 91a 91b 91c 91d 91d 91d t a All reactions were performed with 0.02 mmol of aziridine, 0.10 mmol of thiol and 0.4 mL of ether. b Determined by TLC. c Determined by chiral HPLC. d Reaction was performed at -50 °C. e Reaction was catalyzed by guanidine 79b. Our initial investigation into the desymmetrization of cis-aziridine-2,3-dicarboxylates involved studying the effect of substitution on the nitrogen atom of the aziridine with aminoindanol derived guanidine 79a as the catalyst (Table 2.9). When Cbz was employed as the protecting group on the nitrogen atom, cis-di-tert-butyl aziridine-2,3-dicarboxylate 91b provided the ring-opened product with higher enantioselectivity (55% ee) than that of the less hindered aziridine 91a (entries 1-2). However, the reaction rate of 91b was much slower. Unexpectedly, the use of 3,5-dinitrobenzoyl group as the substituent resulted in very low enantioselectivity (8% ee, entry 3). Tosyl group was found to be the ideal substituent on the nitrogen atom of the aziridine. The reaction rate was much faster albeit with a slightly lower ee value 50 Chapter (51%, entry 4). The enantiomeric excess could be further improved to 68% when the reaction was conducted at lower temperature -50 °C (entry 5). Replacement of the guanidine catalyst 79a with 79b bearing TBDPS group resulted in higher enantioselectivity (72% ee, entry 6). Table 2.10 Solvent and concentration effects on the desymmetrization of cis-aziridine-2,3-dicarboxylate 91d with benzenethiol 63c catalyzed by guanidine 79b.a entry solvent 7c 9d ether toluene DIPE MTBE DIPE DIPE DIPE DIPE DIPE concentration /M 0.05 0.05 0.05 0.05 0.10 0.025 0.025 0.0125 0.005 time /h 36 36 36 48 36 40 72 48 48 ee /%b 77 78 85 80 82 87 88 88 90 a All reactions were performed with 0.02 mmol of aziridine, 0.10 mmol of thiol. Determined by chiral HPLC. c Reaction with mol% of catalyst 79b. d Isolated yield, 97%. b To achieve satisfactory enantioselectivity for the desymmetrization of cis-ditert-butyl N-tosyl-aziridine-2,3-dicaboxylate 91d, the effects of solvent and reaction concentration were then investigated using guanidine 79b as the catalyst and 2,6-dimethyl benzenethiol 63c as the nucleophile (Table 2.10). Toluene gave the same level of enantioselectivity as diethyl ether (78% ee, entry 2). Other ether type solvents 51 Chapter like diisopropyl ether (DIPE) and methyl tert-butyl ether (MTBE) gave improved enantioselectivities (85% and 80% ee, respectively, entries 3-4). Nevertheless, MTBE provided the product with slower reaction rate. With diisopropyl ether as the optimum solvent, higher ee values were obtained by reducing the reaction concentration (entries 6-9). At a higher concentration of 0.10 M, only 82% ee was observed (entry 5). When the reaction concentration was diluted to 0.005 M, the enantiomeric excess was increased to 90% (entry 9). Decreasing the catalyst loading to mol% also slightly increased enantioslectivity but the reaction rate was obviously slowed down (entry 7). 2.4.3 Enantioselective desymmetrization of cis-di-tert-butyl N-tosyl-aziridine-2,3-dicaboxylate with various thiols In order to establish the generality of the reaction, we focused on the variation of the thiol substrate (Table 2.11). Unsubstituted benzenethiol gave 82% ee (entry 1). Both 1-and 2-naphthalenethiol were tested and the same ee value (80%) was obtained (entries 2-3). 4-Bromo benzenethiol gave the best enantioselectivity (85% ee) among the para-substituted benzenethiols that were screened (entries 4-6). The electron-donating mono ortho-substituent resulted in higher enantioselectivity than that of electron- withdrawing substituent (entries 7-9). When two Cl atoms were introduced to the 2,6-positions of benzenethiol, the corresponding product was obtained with 88% ee (entry 10). 2,4,6-Trimethyl benzenethiol also afforded good enantioselectivity but with longer reaction time (87% ee, entry 11). 3,5-Dimethyl benzenethiol provided the product with relatively lower ee value (74%, entry 12). 52 Chapter Table 2.11 Desymmetrization of cis-aziridine-2,3-dicarboxylate 91d with various thiols catalyzed by guanidine 79b.a product time /h ee /%b 92d 36 82 93b 40 80 93c 40 80 93d 36 74 93e 36 85 93f 72 73 93g 72 30 93h 72 67 93i 72 74 entry thiol 53 Chapter 10 93j 48 88 11 93k 72 87 12 93l 72 74 a All reactions were performed with 0.02 mmol of aziridine, 0.10 mmol of thiol and mL of diisopropyl ether. b Determined by chiral HPLC. 2.5 Conclusion In this chapter, we have developed a novel chiral guanidine 79b as an efficient Brønsted base catalyst for the desymmetrization of meso-aziridines. The catalyst was readily prepared from commercially available (1R,2R)-1-amino-2-indanol. With this catalyst, a variety of meso N-acyl aziridines derived from both cyclic and acyclic alkanes reacted with arenethiols to provide β-acylamino thioethers in high yields and enantioselectivities. Chiral allylic amides were synthesized from the ring-opened products by two steps. This guanidine catalyst was also successfully employed in the desymmetrization of cis-N-tosyl-aziridine-2,3-dicaboxylates with arenethiols. This is a direct synthetic approach towards chiral β-substituted aspartates. Given that both enantiomers of trans-1-amino-2-indanol are commercially available, chiral products with the opposite configuration could also be prepared readily. However, the reaction mechanism is not clear. Future work will include theoretical and experimental studies into the mechanism of this asymmetric ring opening reaction. 54 Chapter References: [1] Yamamoto, Y.; Kojima, S. in: The Chemistry of Amidines and Imidates, Patai, S.; Rappoport, Z., Eds., John Wiley & Sons Inc.: New York, 1991, Vol. 2, pp.485. [2] (a) Chinchilla, R.; Nájera, C.; Sánchez-Agulló, P. Tetrahedron: Asymmetry 1994, 5, 1393. (b) Ma, D.; Pan, Q.; Han, F. Tetrahedron Lett. 2002, 43, 9401. (c) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Adv. Synth. Catal. 2005, 347, 1643. (d) Takada, K.; Takemura, N.; Cho, K.; Sohtome, Y.; Nagasawa, K. Tetrahedron Lett. 2008, 49, 1623. [3] (a) Ma, D.; Cheng, K. Tetrahedron: Asymmetry 1999, 10, 713. (b) Ishikawa, T.; Araki, Y.; Kumamoto, T.; Seki, H.; Fukuda, K.; Isobe, T. Chem. Commun. 2001, 245. (c) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454. [4] Kobayashi, S.; Yazaki, R.; Seki, K.; Yamashita, Y. Angew. Chem., Int. Ed. 2008, 47, 5613. [5] Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044. [6] (a) Iyer, M. S.; Gigstad, K. M.; Namdev, N. D.; Lipton, M. J. Am. Chem. Soc. 1996, 118, 4910. (b) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157. [7] Kita, T.; Georgieva, A.; Hashimoto, Y.; Nakata, T.; Nagasawa, K. Angew. Chem., Int. Ed. 2002, 41, 2832. [8] Kitani, Y.; Kumamoto, T.; Isobe, T.; Fukuda, K.; Ishikawa, T. Adv. Synth. Catal. 2005, 347, 1653. [9] Allingham, M. T.; Howard-Jones, A.; Murphy, P. J.; Thomas, D. A.; Caulkett, P. W. R. Tetrahedron Lett. 2003, 44, 8677. 55 Chapter [10] Isobe, T.; Fukuda, K.; Araki, Y.; Ishikawa, T. Chem. Commun. 2001, 243. [11] Basavaiah, D.; Rao, K. V.; Reddy, B. S. Tetrahedron: Asymmetry 2006, 17, 1036. [12] Isobe, T.; Fukuda, K.; Ishikawa, T. Tetrahedron: Asymmetry 1998, 9, 1729. [13] Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737. [14] Hjelmencrantz, A.; Berg, U. J. Org. Chem.2002, 67, 3585. [15] Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228. [16] Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H. Tetrahedron Lett. 2006, 47, 1007. [17] Ye, W.; Jiang, Z; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh, Y.-T.; Tan, C.-H. Adv. Synth. Catal. 2007, 349, 2454. [18] Jiang, Z; Ye, W.; Yang, Y.; Tan, C.-H. Adv. Synth. Catal. 2008, 350, 2345. [19] Fu, X.; Jiang, Z; Tan, C.-H. Chem. Commun. 2007, 5058. [20] Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C.-H. Angew. Chem., Int. Ed. 2008, 47, 5641. [21] Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.; Xu, J.; Tan, C.-H. J. Am. Chem. Soc. 2006, 128, 13692. [22] Fu, X.; Loh, W.-T.; Zhang, Y.; Chen, T.; Ma, T.; Liu, H.; Wang, J.; Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 7387. [23] (a) Soh, Y.-T.; Tan, C.-H. J. Am. Chem. Soc. 2009, 131, 6904. (b) Senanayake, C. H.; Krishnamurthy, D.; Gallou, I. in: Handbook of Chiral Fine Chemicals, 56 Chapter Ager, D., Eds., Taylor Francis: New York, 2005. (c) Gallou, I.; Senanayake, C. H. Chem. Rev. 2006, 106, 2843. [24] Tanner, D. Angew. Chem, Int. Ed. Engl. 1994, 33, 599. [25] Kesavan, V.; Danièle, B.-D.; Bgéué, J.-P. Tetrahedron Lett. 2000, 41, 2895. [26] Bucciarelli, M.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. J. Chem. Soc., Perkin Trans. 1993, 3041. [27] Antolini, L.; Bucciarelli, M.; Caselli, E.; Davolli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. J. Org. Chem. 1997, 62, 8784. [28] Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612. [29] Rinaudo, G.; Narizuka, S.; Askari, N.; Crousse, B.; Bonnet-Delpon, D. Tetrahedron Lett. 2006, 47, 2065. 57 [...]... catalyzed desymmetrization of meso- aziridines 4a, 1a with benzenethiol 63a.a entry aziridine catalyst temp /° C time /h conversion /%b ee /%c 1 2 3 4 5 6 7 8 4a 4a 4a 4a 1a 1a 1a 1a 79a 73 79b 79c 79a 79b 79c 79d 25 25 -20 -20 -20 -20 -20 -20 24 24 24 24 20 20 20 20 100 100 90 90 94d 94d 89d 92d 15 13 30 17 4 33 2 2 a All reactions were performed with 0. 02 mmol of aziridine, 0.04 mmol of thiol and 0.8 mL of. .. temperature, 34 Chapter 2 Table 2. 2 Solvent effect on the chiral guanidine 39 catalyzed desymmetrization of meso N-tosyl aziridine 4a with benzenethiol 63a a entry time /h conversion /%b ee /%c 1 2 3 4 5 6 a solvent ether THF toluene MeOH MeCN CH2Cl2 24 24 24 14 20 24 100 100 90 100 100 0 29 20 25 0 0 n.d All reactions were performed with 0. 02 mmol of aziridine, 0.1 mmol of thiol and 0 .2 mL of solvent b Determined... the desymmetrization of acyclic meso- aziridines bearing aliphatic and aryl substituents (entries 6-7) Aziridine 44 Chapter 2 Table 2. 8 Desymmetrization of various meso N-3,5-dinitrobenzoyl aziridines 12 with benzenethiol 63d catalyzed by guanidine 79b.a product x mol% temp /° C time /h yield /%b ee /%c 1 81c 1 -50 48 92 94 2 82a 2 2 -50 -20 72 48 89 93 84 90 3 82b 1 1 -50 -20 48 60 91 94 89 94 4 82c 2. .. -20 48 60 91 94 89 94 4 82c 2 5 5 -50 -50 -20 72 72 72 67 85 91 91 92 95 5 82d 5 -20 72 90 90 6 82e 2 -20 48 91 93 7 82f 2 5 -20 -20 48 48 81 93 75 88 entry 12 (R=3,5-dinitrobenzoyl) a All reactions were performed with 0.05 mmol of aziridine, 0.1 mmol of thiol and 5 mL of ether b Isolated yield c Determined by chiral HPLC 45 Chapter 2 12h reacted smoothly with 2, 6-dichloro benzenthiol 63d to afford the... Chapter 2 Scheme 2. 17 Synthesis of guanidinium salts from O-protected aminoindanols 2. 3 Guanidine catalyzed enantioselective desymmetrization of meso N-acyl aziridines with thiols 2. 3.1 Optimization studies on the enantioselective desymmetrization of meso N-acyl aziridines Preliminary studies showed that the desymmetrization of N-tosyl aziridine 4a with benzenethiol 63a could be catalyzed by 10 mol% of. .. 63d.a entry x mol% time /h yield /%b ee /%c 1 2 3d 4d 5 2 2 1 20 24 24 40 93 93 92 92 89 91 92 92 a All reactions were performed with 0. 02 mmol of aziridine, 0.04 mmol of thiol and 0.8 mL of ether b Isolated yield c Determined by chiral HPLC d With 2. 0 mL of ether It was found that the enantioselectivity of the desymmetrization of meso N-acyl aziridine 12a with benzenethiol 63d could be further improved... 52 Chapter 2 Table 2. 11 Desymmetrization of cis-aziridine -2, 3-dicarboxylate 91d with various thiols catalyzed by guanidine 79b.a product time /h ee /%b 1 92d 36 82 2 93b 40 80 3 93c 40 80 4 93d 36 74 5 93e 36 85 6 93f 72 73 7 93g 72 30 8 93h 72 67 9 93i 72 74 entry thiol 53 Chapter 2 10 93j 48 88 11 93k 72 87 12 93l 72 74 a All reactions were performed with 0. 02 mmol of aziridine, 0.10 mmol of thiol... presence of carbobenzyloxy chloride (CbzCl) or 3,5-dinitrobenzoyl chloride with NaHCO3 as base, or tosyl chloride (TsCl) with pyridine as base .29 Scheme 2. 20 Synthesis of cis-aziridine -2, 3-dicarboxylates 49 Chapter 2 2.4 .2 Optimization studies on the enantioselective desymmetrization of cis-aziridine -2, 3-dicaboxylates Table 2. 9 Chiral guanidine 79a catalyzed desymmetrization of various cis-aziridine2,3-dicarboxylates... catalyzed desymmetrization of meso- aziridines 47 Chapter 2 The catalytic cycle of the chiral guanidine 79b catalyzed desymmetrization of meso- aziridines with benzenethiols was proposed as in Scheme 2. 19 We reasoned that the guanidine group would deprotonate benzenethiol, generating an association in the guanidine- thiol complex 85 In the first step of the cycle, meso- aziridine 12a undergoes nucleophilic... and the same enantioselectivity ( 92% ee) was obtained, albeit longer reaction time was required (entry 4) 2. 3 .2 Highly enantioselective desymmetrization of meso N-acyl aziridines with thiols With the optimized conditions in hand, we next investigated the desymmetrization of a wide range of meso N-3,5-dinitrobenzoyl aziridines 12 with 2, 6-dichloro benzenethiol 63d (Table 2. 8) In general, high yields and . Chapter 2 23 Chapter 2 Guanidine Catalyzed Enantioselective Desymmetrization of meso- Aziridines with Thiols Chapter 2 24 2. 1 Bicyclic guanidine catalyzed. Scheme 2. 12 Chiral bicyclic guanidine catalyzed Diels-Alder reactions of anthrones. 21 Chapter 2 33 2. 1 .2 Bicyclic guanidine catalyzed enantioselective desymmetrization of meso. 79a 25 24 100 15 2 4a 73 25 24 100 13 3 4a 79b -20 24 90 30 4 4a 79c -20 24 90 17 5 1a 79a -20 20 94 d 4 6 1a 79b -20 20 94 d 33 7 1a 79c -20 20 89 d