Chapter Chapter Pentanidium Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions 31 Chapter 2.1 Introduction to Asymmetric Phase-Transfer Catalyzed Conjugate Addition of Glycinate Schiff base Compounds with active methylene or methine groups could easily undergo asymmetric conjugate addition with electron-deficient olefins, particularly αβ-unsaturated carbonyl compounds to afford various functionalized products, which represents an important route for C-C bond formation asymmetric organic synthesis.1 Various functionalized α-alkyl amino acids have been synthesized by enantioselective conjugate addition of glycinate derivatives by chiral phase-transfer catalysis. Corey et al. utilized cinchonidinium bromide 11 as a chiral phase-transfer catalyst for the asymmetric Michael addition of glycinate Schiff base to αβ-unsaturated carbonyl substrates with high enantioselectivities (Scheme 2.1).2 α-Tert-butyl γ-methyl ester of (S)-glutamic acid, which is highly useful in synthetic applications, could be synthesized by using methyl acrylate as Michael acceptor. Besides, when acrylonitrile was used as an acceptor, product 55c could be easily transformed to diaminoacid 56 (Scheme 2.1).2 O’Donnell et al. conducted the Michael addition in a wider scope with the organic-soluble bases BEMP and BTPP, including acrylate, acrylonitrile, vinyl ketone, and unsaturated sulfone. These representative Michael acceptors were more tolerated under less basic BEMP condition, excellent yield and ee were achieved (Scheme 2.2). 32 Chapter Scheme 2.1 Highly enantioselective Michael reactions of with catalyst 11. Scheme 2.2 Organic-soluble base BEMP in phase-transfer system In 2002, Arai et al. developed and applied in the asymmetric Michael addition of with acrylate using tartrate-based spiro chiral ammonium salt 57 as phase-transfer catalyst, only moderate ee and yield was observed (Scheme 2.3).4 Later, Arai’s group synthesized a new binaphthyl-derived bis(ammonium)salt 58 as an efficient chiral phase-transfer catalyst for the Michael addition reactions (Scheme 2.4). Though only moderate ee was achieved, the most advantage is that the modification on the ether and ammonium moieties seems quite convenient.5 33 Chapter Scheme 2.3 Tartrate-based spiro chiral ammonium salt 57 as phase-transfer catalyst Scheme 2.4 Chiral binaphthyl-derived bis(ammonium) salt 58 as phase-transfer catalyst Scheme 2.5 Tartrate-derived bis(ammonium) salts 59 as phase-transfer catalysts Shibasaki and co-workers also invented tartrate-derived, C2-symmetric bis(ammonium) salts 59 as phase-transfer catalysts and successfully applied them to the asymmetric Michael addition of to benzyl acrylate (Scheme 2.5).6 Counter-ion 34 Chapter has a significant effect on yield. Changing counter ion from iodide (I-) to tetrafluoroborate (BF4-) could dramatically accelerate the reaction and improve the yield. Besides ammonium salt, Akiyama et al. developed a chiro-inositol-derived crown ether 60 as phase-transfer catalyst, which showed good reactivity and selectivity of the asymmetric Michael addition of glycinate Schiff base 1.7 High levels of enantioselectivities were achieved for both alkyl vinyl ketone and acrelate (Scheme 2.6). Scheme 2.6 Chiro-inositol-derived crown ether as a phase-transfer catalyst. Lygo’s group utilized the quaternary ammonium salt, 61 derived from (α-naphthylmethyl)-amine, as phase-transfer catalyst to study the reaction parameters for the asymmetric Michael addition of a glycine diphenylmethyl ester Schiff base 62 to alkyl vinyl ketone 54d, 54i. High level of enantioselectivities can be obtained by conducting reaction in diisopropyl ether at oC in the presence of 50 mol% Cs2CO3 and mol% catalyst (Scheme 2.7).8a Later, Lygo’s group also found that adding mesitol to the reaction could dramatically enhance the reaction rate in the KOH 35 Chapter mediated enantioseletive Michael addition reaction. It was revealed that mesitol played a role of co-catalyst.8b Scheme 2.7 α-Methylnaphthylamine-derived ammonium salt 61 as phase-transfer catalyst. Scheme 2.8 Asymmetric 1, 6-addition of to electron-deficien diene with and formation of optically active pyrrolidine Jorgensen’s group reported an organocatalytic asymmetric 1, 6-addition of to electron-deficient α,β-unsubstituted dienes 64a-64d to afford the corresponding optically active addition products 65-65d in good yields and excellent enantioselectivities(up to 98% ee), using readily accessible cinchona alkaloid-derived chiral phase-transfer catalyst 8. The synthetic utility of this asymmetric reaction was 36 Chapter illustrated by the formation of an attractive optically active pyrrolidine 66 from 65b (Scheme 2.8).9 In the same year, Jorgensen’s group also reported a highly enantioselective conjugate addition of glycine imine derivatives 67 to electron-deficient allene 6810. Finally, the synthetic value of the chiral products obtained from this reaction was exemplified by their straightforward transformation to optically active 2, 3-disubstituted γ-lactams 70 (Scheme 2.9). Scheme 2.9 Enantioselective conjugate addition of 67 to allene 68 and synthesis of optically active 2, 3-disubstituted γ-lactams Maruoka’s catalysts (13, 14, 15) showed excellent reactivity towards various phase-transfer catalyzed reactions. In the additive screening experiments, it was found that CsCl played a role of rate enhancement in the phase-transfer catalyzed conjugate additions of to acrylate (Scheme 2.10). 11a With respect to the enantioselectivity and cost, a combination of K2CO3 and catalytic CsCl is clearly superior to Cs2CO3, which affords the same result as Cs2CO3. 37 Chapter When this strategy (asymmetric conjugate addition with CsCl as additive) is applied to alkyl vinyl ketone, product could be easily transformed to chiral disubstituted pyrolidine 75 (Scheme 2.11).11b Various functionalized vinyl ketones lead to one-pot synthesis of hexahydropyrrolizine 78a, and octahydroindolizine core 78b structures (Scheme 2.12). This approach allows the facile synthesis of a natural alkaloid such as (+)-Monomorine.11b Scheme 2.10 Enantioselective conjugate addition of with CsCl as additive Scheme 2.11 Enantioselective conjugate addition with ethyl acrylate and synthesis of 2, 5-disubstituted cis-pyrrolidine 75 Scheme 2.12 Synthesis of hexahydropyrrolizine 78a and octahydroindolizine 78b 38 Chapter Summary The conjugate addition reactions of glycine ester derivatives with various αβunsaturated carbonyl compounds were introduced. These reactions provide optical active compounds with high yields and excellent enantioselectivities, which could be easily transformed to several chiral building blocks, such as chiral γ-lactames, pyrrolidine, hexahydropyrrolizine and α-amino acid derivatives. However, among them, all of the Michael acceptors are electron-deficient terminal alkenes, no αβ-unsaturated-β-substituted carbonyl compound was reported to realize conjugate addition with glycine ester derivatives. So a more general phase-transfer catalyst for both types of acceptors is reasonably required. 39 Chapter 2.2 Introduction to pentanidium and synthesis of chiral pentanidium We have developed bicyclic guanidine as chiral Brønsted base catalyst for enantioselective reactions over the past several years.12 As an extension of this work, we began a program to develop novel structures that are more basic than guanidine. We naively developed structures containing five nitrogen atoms in conjugation, pentanidine, with the hypothesis that this may render it more basic than guanidine. Serendipitously, we found that its alkylated salt, pentanidium, turns out to be an excellent phase-transfer catalyst. Herein, we wish to introduce a novel C2-symmetric chiral pentanidium and its successful application to catalytic enantioselective conjugate addition of tert-butyl glycinate-benzophenone Schiff base to variousαβ-unsaturated acceptors, including vinyl ketones, acrylates and chalcones. The IUPAC name for the 5-nitrogen core is diaminomethylidene guanidine and some authors refer to it as biguanide. To avoid confusion with guanidine or bis-guanidine, we describe it as pentanidine (for base) or pentanidium (for salt). Only few examples of this structure were shown in literatures. Early 1966, Bauer synthesized octamethylbiguanide perchlorate as the most highly substituted biguanide (Figure 2.1). 13 Large numbers of biguanides have been known as potential antimalarial drugs and as hypoglycemic agents. Figure 2.1 Most highly substituted biguanide 40 Chapter a toluene 3h 100 77 Et2O 7h 100 73 Et2O(dehydrated) 7h 100 73 TBME 12h 100 75 ethyl benzene 3h 100 81 m-xylene 6h 100 83 p-xylene 24h 30 50 mesitylene 4h 100 87 styrene 24h [...]... (%)c 1 Ph, Ph 89a 12 98 92 2 Ph, 1-naphthyl 89b 12 91 92 3 Ph, 2- naphthyl 89c 24 93 90 4 Ph, 4-PhC6H4 89d 21 88 91 54 Chapter 2 5 Ph, 4-FC6H4 89e 18 89 90 6 Ph, 4-ClC6H4 89f 15 98 92 7 Ph, 4-BrC6H4 89g 15 96 92 8 Ph, 4-NO2C6H4 89h 10 91 94 9 Ph, 2- ClC6H4 89i 12 93 94 10 Ph, 4-MeOC6H4 89j 36 89 85 11 4-ClC6H4, Ph 89k 12 90 92 12 4-NO2C6H4, Ph 89l 12 91 91 13 4-MeOC6H4, Ph 89m 18 83 87 14 2- naphthyl, Ph... 73 3 Et2O(dehydrated) 7h 100 73 4 TBME 12h 100 75 5 ethyl benzene 3h 100 81 6 m-xylene 6h 100 83 7 p-xylene 24 h 30 50 8 mesitylene 4h 100 87 9 styrene 24 h . (Scheme 2. 2). Chapter 2 33 Scheme 2. 1 Highly enantioselective Michael reactions of 1 with catalyst 11. Scheme 2. 2 Organic-soluble base BEMP in phase-transfer system In 20 02, Arai et. 2 31 Chapter 2 Pentanidium Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions Chapter 2 32 2. 1. Ag 2 CO 3 24 h 50 3 10 CsOH·H 2 O 10min 100 40 11 LiOH·H 2 O 2h 50 31 12 d CsF(5 eq) 12h 80 71 a Reactions were performed by using 1 (0. 02 mmol), and 54b (0.04 mmol) in 0.2