Enantioselective Protonation Catalyzed by Chiral Brønsted Bases

1 1 2 2 1, Chao Wang, Cindy Mei Ting Goh, Shihua Xiao, Weiping Ye, and Choon ─ Hong Tan ＊

1 School of Physical & Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University 21 Nanyang Link, 637371, Singapore 2 Raes PharmaTech Co Ltd No 5, Keji Road, Science and Technology Innovation Industrial Park, Dayawan, Huizhou, Guangdong, China

(Received July 1, 2013; E ─ mail: [email protected])

Abstract: The proton is the smallest group in synthetic organic chemistry. Moving a proton within a catalytic cycle in an enantioselective manner is a formidable task that has attracted the attention of many chemists. Furthermore, catalytic enantioselective protonation is an atom economical method of generating chiral carbon centers. Variations of this kind of reaction catalyzed by transition metals catalysts have been well investigated. On the other hand, a complementary approach to this reaction, the use of chiral Brønsted base catalysts is relatively less explored. We have developed several protonation reactions using chiral bicyclic guanidine as the Brønsted base catalyst. In this review, we will report these reactions and other related examples recently described by other groups.

Scheme 2. Catalytic enantioselective conjugate addition ─ enantio- 1． Introduction selective protonation with chiral metal complexes. The proton is the smallest group in synthetic organic chemistry. Moving a proton within a catalytic cycle in an enantioselective manner is a formidable task that has attracted the attention of many chemists. Furthermore, enantioselective protonation of tertiary carbanion intermediates is a funda- mental and useful method of generating stereogenic carbon centers. 1 This method is commonly used in enzyme catalyzed biosynthetic asymmetric transformations. 2 It involves the generation of a deprotonated enolate using a base, followed by kinetic protonation using a stoichiometric amount of a chiral proton source. Over the past several decades, catalytic enantioselective protonation reactions such as those that involve the use of a catalytic amount of protonating agent and in situ gene- goes protonation by the conjugate acid of the catalyst in an ration of a prochiral enolate, have been widely studied. Chiral enantioselective manner. In a Brønsted base─ catalyzed isomeri- Lewis acids 3 and Brønsted acids 4 have been shown to be effec- zation process, a proton is abstracted from the reactant by the tive catalysts in the enantioselective protonation of preformed basic catalyst and this or another proton on the catalyst is enolates (Scheme 1). In addition, in situ generation of enolates returned to the reactant in an enantioselective manner. For is an effective strategy which has been ful lled through asymmetric catalysis with transition metals (Scheme 2). 5,6 Scheme 3. Brønsted base ─ catalyzed enantioselective protonation Several strategies have been developed for Brønsted base ─ reactions (B＊ =chiral Brønsted base). catalyzed enantioselective protonation reaction (Scheme 3). In a conjugate addition ─ enantioselective protonation reaction, the catalyst activates the nucleophile, which adds to an electro- phile to generate a transient enolate. This enolate then under-

Scheme 1. Catalytic enantioselective protonations of enol silanes with chiral Lewis acids and Brønsted acids.

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有機合成化学71-11＿05論文_Wang.indd 37 2013/10/21 11:45:08 racemic compounds, deracemization is impossible as deproto- Table 1. Enantioselective protonation of tert ─ butyl nation and protonation is reversible. However, enantiomeric 2 ─ phthalimidoacrylate with thiols. enrichment of racemic compounds can be achieved through H ─ D exchange under Brønsted base catalysis. In this review, we will discuss the application of Brønsted bases to catalytic enantioselective protonation reactions. We will present methodology developed in our laboratory using chiral bicyclic guanidines as well as related reactions developed recently by other groups. An improved procedure for the synthesis of bicyclic guanidine catalyst will also be revealed. 2． Brønsted Base catalyzed Conjugate Addition enantioselective Protonation ─ ─ The generation of a transient enolate through a conjugate addition reaction can be an ef cient strategy for enantioselective protonation. Both chiral Lewis acid catalyst 5,6 and chiral Brønsted base approaches have been employed. Seminal work on tandem conjugate addition ─ enantioselective protonation was reported by Pracejus in 1977. 7 The reaction between methyl 2 ─ phthalimidoacrylate and phenylmethanethiol catalyzed by Cinchona alkaloids produced cysteine esters with moderate enantioselectivities. Chen reported the conjugate addition of thiophenol to α ─ substituted acrylamide followed by enantioselective protonation with enantioselectivities of up to 60% ee. 8 An enantioselective conjugate addition reaction followed by diastereoselective protonation of non ─ adjacent chiral centers was described by Deng. 9 In addition, Fu reported

a planar ─ chiral heterocycle ─ catalyzed addition of HN 3 to ketenes with subsequent Curtius rearrangement at elevated temperatures to afford chiral carbamate products with high enantioselectivities. 10 The chiral heterocycle catalyst acts as a Brønsted base and readily deprotonates hydrazoic acid and stereoselectively protonates the enolate intermediate. nation of 3D structures of proteins 13 and are useful for the For the past few years, we have been interested in the deve- study of mechanisms of enzymatic reactions. We modi ed the

lopment of general chiral Brønsted base catalysts. We found protocol to introduce D 2O and were able to achieve a tandem that chiral guanidine, and particularly, di ─ tert ─ butyl guanidine conjugate addition ─ enantioselective deuteration reaction with 1 (Figure 1), have excellent catalytic activity and display a high high enantioselectivity and high level of deuteration. For level of stereocontrol in a series of organic transformations, example, 4 ─ aminobenzenethiol (2j) was pre ─ stirred in a mix- 11 including several enantioselective protonation reactions. ture of diethyl ether and D 2O (5:1) in the presence of the guanidine catalyst (10 mol%; Scheme 4). After half an hour at ambient temperature, the reaction mixture was cooled down to

- 50 ℃ and D 2O was frozen out of the reaction mixture. The phthalimidoacrylate 3a was then added and within an hour,

Figure 1. Chiral bicyclic guanidine catalyst 1. the reaction reached completion to produce [D 1]4j.

We studied the protonation reactions of tert ─ butyl 2 ─ Scheme 4. Enantioselective deuteration of tert ─ butyl 2 phthalimidoacrylate (3a). phthalimidoacrylate with various thiols. In the presence of our ─ chiral bicyclic guanidine catalyst, cysteine analogues were formed with high enantioselectivities and high yields (Table 1). Various phthalimidoacrylates were developed and examined in this reaction to allow exibility in the deprotection step. It was also found that substituents on the N ─ phthalimide protecting group did not affect the enantioselectivities greatly. Alkyl thiols are generally more reactive, hence the uncatalyzed reactions of Similarly, the addition of secondary phosphine oxides to alkyl thiols are usually more pronounced. High enantioselec- N ─ substituted itaconimides proceeded smoothly in the prese- tivity was achieved in the reaction between phthalimidoacry- nce of the guanidine catalyst (10 mol%) at 0 ℃. Reactions late and an unusual diphenylmethanethiol, affording an adduct between N ─ (2,4,6 ─ trimethylphenyl)itaconimide and the seco- which can be readily converted into a free thiol. ndary phosphine oxides reached completion within several Asymmetric deuteration of enolates is a common method hours, producing chiral cyclic imides in high yields and with 12 used to prepare chiral α ─ deuterated carbonyl compounds. high ee values (Table 2). Deuterated amino acids play an important role in the determi- In order to understand the catalytic mechanism and the

1 146 （ 38 ） J. Synth. Org. Chem., Jpn.

有機合成化学71-11＿05論文_Wang.indd 38 2013/10/21 11:45:12 Table 2. Enantioselective protonation of N ─ (2,4,6 ─ trimethylphenyl)- guanidine proceeded smoothly. After optimizing the reaction itaconimide (6) with secondary phosphine oxides. conditions, chiral allenoates can be obtained with high enantioselectivities. Various 4 ─ aryl 3 ─ alkynoates (8) were investigated under the optimized reaction conditions (Table 3). Both electron ─ withdrawing and electron ─ donating substituents have no effect on the reactivity and ee values. The allenes were insepa- rable from the unreacted alkynes, except for allenoates 9g and 9h. The bulky ester group was found to be a prerequisite for the reaction to achieve high ee.

Table 3. Enantioselective isomerization of 4 ─ aryl 3 ─ alkynoates (8).

origin of the stereoselectivity, density functional theory (DFT) calculations were performed for the reaction between thiophe- 14 nol and tert ─ butyl 2 ─ phthalimidoacrylate. An unconven- tional bi ─ functional activation involving guanidinium, which serves simultaneously as a Lewis acid via the electrophilic cen- tral carbon, and also as a Brønsted acid, was revealed (Scheme 5). This intriguing activation mode critically inu- ences the stereoselectivity of the thio ─ Michael addition product. Hetero ─ substituted (X=O or N) alkynoates underwent Scheme 5. Bifunctional activation mode by guanidinium. isomerization smoothly to give allenoates with high enantioselectivity (Table 4). The propargylic alcohol 10a, tertiary propargylic alcohol 10b and O ─ benzyl (Bn) protected propargylic alcohol 10c were good examples. Interestingly, N ─ Phthalimido (PhthN) protected propargylic amine 10e gave excellent conversion.

Table 4. Enantioselective isomerization of 5 ─ functionalized allenoates (10).

3． Brønsted Base catalyzed Asymmetric Isomerization Reaction ─ Allenes can be found in many natural products and biological active compounds; 15 they are also important intermediates in organic synthesis. 16 Most chiral allenes are prepared via chirality transfer from enantiomerically pure propargyl alcohols due to the ready availability of these alcohols. There are relatively fewer examples of their preparation that use enantioselective catalysts and pro ─ chiral starting materials. Although allenes can be prepared directly from alkynes through a Brøn- 17 sted base catalyzed 1,3 ─ proton shift, only one attempt at catalytic asymmetric isomerization of alkynes to allenes has been 18 reported thus far. This was carried out under chiral phase ─ DFT calculations using B3LYP were carried out to evalu- transfer catalysis and moderate enantioselectivities were ate the relative stabilities of selected alkyne/allene isomer pairs. observed. All allenes studied are found to be more stable than the corre- We were pleased to nd that the isomerization of function- sponding alkynes. The calculated ΔG values were also found to alized 3 ─ alkynoates to allenoates catalyzed by our bicyclic correlate well with the observed yields.

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有機合成化学71-11＿05論文_Wang.indd 39 2013/10/21 11:45:17 Cycloaddition reactions of allenoates and dienes have been chiral cyclohex ─ 2 ─ enones can be obtained from anisoles via a 19 developed as an ef cient strategy in natural product synthesis. 3 ─ step approach. The synthetic utility of this isomerization Diels ─ Alder reaction of the allenoate 11e with cyclopentadiene reaction was highlighted by the enantioselective synthesis of gave the endo diastereomer 12 as the major product (Scheme 6). (-) ─ isoacanthodoral. High yields were obtained with excellent chirality transfer. 1,3 ─ Proton isomerization of imines, transamination, is an Electrophilic cyclization reactions were also carried out with important process used to generate α ─ amino acids in biologi- the chiral allenes. 20 When a mixture of 8b and 9b was cyclized cal systems. Biomimetic transamination has been reported

with pyridinium tribromide (PyHBr 3), the chiral lactone 14 with Lewis base and Lewis acid catalysts to generate chiral α ─ was obtained in 60% yield and 86% ee, and alkyne 8b was amino acids and their derivatives. 23 Recently, the Shi group recovered quantitatively (Scheme 7). reported the transamination of α ─ keto esters with a quinine analogue as the catalyst and o ─ ClPhCH 2NH 2 as the amine Scheme 6. Cycloaddition of an allenoate with cyclopentadiene. donor, yielding α ─ amino esters with high enantioselectivities and in good yields (Scheme 10). 24a They found that hydrogen bond donors at the 6’ ─ position of quinine have a signi cant effect on the reactivity and enantioselectivity of the reaction. They also discovered that certain substituted benzenesulfon- amide quinine derivatives were highly effective catalysts for this transamination reaction. 24b

Scheme 7. Cyclization reaction with chiral allene. Scheme 10. Transamination of α ─ keto esters.

Deng reported a highly enantioselective 1,3 ─ proton isomerization of β,γ ─ butenolides to α, β ─ butenolides using QD 15 21 ─ as a catalyst (Scheme 8). A broad range of β,γ ─ butenolides bearing one or more substituents were isomerized to chiral α, β ─ butenolides in up to 95% yield and 94% ee. Mechanistic studies indicate that the protonation step is the rate ─ determin- ing step of this organocatalytic ole n isomerization. Similarly, the catalytic enantioselective isomerization of N ─ benzyl triuoromethyl imines via a 1,3 ─ proton shift is an Scheme 8. 1,3 ─ Proton isomerization of β,γ ─ butenolides. attractive strategy for the asymmetric synthesis of chiral triuoromethylated amines. 25 Recently, the Deng group found that 9 ─ OH cinchona alkaloid, DHQ 18, is an effective catalyst for this isomerization (Scheme 11).─ 26 This reaction provides an approach to both aryl and alkyl triuoromethylated amines in up to 81% yield and 94% ee.

Scheme 11. Transamination of triuoromethylated imine. Following this, the same group reported a catalytic enantioselective isomerization of β,γ ─ unsaturated cyclohex ─ 3 ─ en ─ 1 ─ 22 ones to α, β ─ unsaturated chiral enones (Scheme 9). Notably, this asymmetric isomerization was realized by the cooperative iminium ─ base catalysis with an electronically tunable organic catalyst. Using this transformation, a series of optically active

Scheme 9. Isomerization of β,γ ─ unsaturated to α, β ─ unsaturated enones. 4． Brønsted Base catalyzed Asymmetric H D Exchange Reaction ─ ─ Enantiomeric enrichment of racemic molecules via reversible deprotonation and protonation using a chiral catalyst is not possible under thermodynamic conditions. However, enantiomeric enrichment can be achieved through H ─ D exchange reaction using a source of deuterium. Recently, we disclosed the rst asymmetric H ─ D exchange reaction of α ─ uorinated aromatic ketones catalyzed by chiral guanidine. We found that

in the presence of 150 equivalents of D 2O and 30 mol% of the bicyclic guanidine catalyst, the deuterated product was obtained with an ee value of 18% and with 70% deuterium

1 148 （ 40 ） J. Synth. Org. Chem., Jpn.

有機合成化学71-11＿05論文_Wang.indd 40 2013/10/21 11:45:21 incorporation after 12 hours (Table 5). After screening a series round ─ bottom ask was tted with a magnetic stir bar, a reux of solvents, we found that the best result was obtained with condenser and an addition funnel. The ask was charged with dichloroethane when the deuterated product was obtained sodium borohydride (83 g) and THF (2 L). To the resulting with 24% ee and 100% deuterium incorporation. Results were suspension, L ─ tert ─ leucine (120 g) was added in one portion. further improved by using α ─ uorinated ketone 19b. 30% ee of A solution of iodine (231 g) in THF (760 mL) was added drop- the deuterated product was then obtained. These results dem- wise through the addition funnel over 30 min at 0 ℃. After onstrate the possibility of achieving enantioenriched adducts evolution of hydrogen gas ceased, the reaction mixture was in an asymmetric H ─ D exchange reaction by using a chiral heated to reux for 18 h and then cooled to 0 ℃. Methanol catalyst. (300 mL) was added cautiously until the mixture become clear, then the solvent was removed with rotary evaporator to obtain Table 5. Asymmetric H ─ D exchange reaction of α ─ uorinated a white paste, which was then dissolved in 20% aqueous KOH ketone. (800 mL). The solution was stirred for 4 h and then was extracted with methylene chloride (1.5 L×3). The organic extracts were dried over sodium sulfate and concentrated in vacuo to obtain a white solid I (97 g, 90%). (S) ─ 2 ─ tert ─ Butyl ─ 1 ─ tosylaziridine (II): To a ame dried round ─ bottom ask containing 4 Å molecular sieves and a magnetic bar, L ─ tert ─ leucinol (97 g), Et 3N (465 mL, 4 equiv.) and dry MeCN (2.3 L) were added. The reaction mixture was cooled to 0 ℃ and then TsCl (173 g, 1.1 equiv.) was added in one portion. After being stirred at 0 ℃ for 20 min, the reaction mixture was brought to room temperature and stirred for another 1 h. The solvent was removed under reduced pressure and ethyl acetate (500 mL) was added. The resulted precipitate and molecular sieves were removed by suction ltration and DFT calculations were carried out to examine this asym- washed thoroughly with ethyl acetate. The ltrate and wash- metric H ─ D exchange reaction. The results suggest the involve- ings were combined, the solvent was removed and the residual ment of water ─ assisted protonation/deprotonation processes oil was treated with a solution of Et 3N (465 mL, 4 equiv.) and and the overall activation free energy was found to be 16.4 and DMAP (10 g, 0.1 equiv.) in dry CH 2Cl 2 (2.3 L). MsCl (126 mL, 1 17.0 kcal mol － , for S ─ 19b and R ─ 19b, respectively. Isotope 2 equiv.) was added slowly to this mixture which was then effects were estimated using frequency calculations and the stirred at room temperature for 1 h. Hydrochloric acid was results indicate that the overall activation free energies for both added until the pH of the solution reached 2. The aqueous deuterated transition states are increased by 1.3 kcal mol －1. phase was extracted with DCM (1 L×3) and the combined The IBM Chemical Kinetics Simulator (CKS) was then used organic layers were evaporated under reduced pressure, the to simulate the possible outcomes of the asymmetric H ─ D residue was recrystallized using petroleum ether and II was exchange reaction with variations in catalyst selectivity and obtained as a white solid (156 g, 80% yield). kinetic isotope effect. A time course study of the overall ee of N,N ’ ─ (2S,2’S ) ─ 1,1’ ─ Azanediylbis(3,3 ─ dimethylbutane ─ 2,1 ─ both H ─ and D ─ α ─ uorinated ketone 19a during the α ─ pro- diyl)bis(4 methylbenzenesulfonamide) (III): NH 3 gas was con- 1 ─ ton exchange monitored using H NMR and chiral HPLC was tinuously bubbled into a solution of aziridine II (260 g) in also performed. We found that the shape of the experimental MeOH (9 L) for 30 min. at 0 ℃. The reaction vessel was sealed plot resembled that of the simulated results. up tightly and brought to room temperature slowly. The mixture was stirred over night, then the solvent was removed under 5 A Protocol for Large scale Preparation of Bicyclic ． reduced pressure, giving a pale yellow oil. This was added to a Guanidine 1 ─ solution of aziridine II (260 g) in dry MeCN (3 L). The reac- We have improved the synthetic procedure for preparing tion mixture was reuxed at 95 ℃ for 3 days. After removing bicyclic guanidine 1 on a larger scale and we would like to solvent under reduced pressure the residue was recrystallized present this result here. from acetonitrile, and III (426 g) was obtained as a white (S) 2 Amino 3,3 dimethylbutan 1 ol (I): A 5 ─ L three ─ neck foamy solid in 80% yield (based on II). ─ ─ ─ ─ ─ ─ (S) N 1 ((S) 2 Amino 3,3 dimethylbutyl) 3,3 dimethylbutane─ 1,2─ diam─ in─e (IV): N─ a (1─20 g, 15 equiv.)─ was─ washed with Scheme 12. Synthesis of bicyclic guanidine 1. ─ ─ hexane and transferred into a 2 L ame dried three ─ necked round ─ bottom ask equipped with a mechanical agitator and a condenser. The reaction ask and the condenser were cooled

to -78 ℃ using dry ice/acetone and NH 3 gas was condensed into the reaction ask until a dark blue solution was formed. While this solution was stirred, a THF solution (1 L) of the triamine backbone III (180 g) was added dropwise to it at -78 ℃. Stirring was continued at -78 ℃ and more Na was added whenever the dark blue color faded. After 4 h, the reaction ask was opened to the air and brought to room tempera-

ture. Solid NH 4Cl was added slowly with vigorous stirring

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有機合成化学71-11＿05論文_Wang.indd 41 2013/10/21 11:45:24 until a white heterogeneous mixture was formed. After all the 3） For selected examples, see: (a) Yanagisawa, A.; Touge, T.; Arai, T. NH had evaporated off, CH Cl (500 mL) was added to the Angew. Chem. Int. Ed. 2005, 44, 1546. (b) Yanagisawa, A.; Touge, T.; 3 2 2 Arai, T. Pure Appl. Chem. 2006, 78, 519. (c) Morita, M.; Drouin, L.; resulting white solid and the mixture was stirred for a half Motoki, R.; Kimura, Y.; Fujimori, I.; Kanai, M.; Shibasaki, M. J. hour. The solid was then removed by suction ltration and was Am. Chem. Soc. 2009, 131, 3858. 4） For selected examples, see: (a) Rueping, M.; Theissmann, T.; Raja, S.; washed with CH 2Cl 2 (500 mL×3). The ltrate and washings were combined and the solvent was removed under reduced Bats, J. W. Adv. Synth. Catal. 2008, 350, 1001. (b) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246. (c) Lee, J. W.; List, pressure, giving a pale yellow oil in quantitative yield. The B. J. Am. Chem. Soc. 2012, 134, 18245. (d) Guin, J.; Varseev, G.; List, crude product was used directly in the next reaction. B. J. Am. Chem. Soc. 2013, 135, 2100. (2S,6S ) 2,6 Di tert butyl 2,3,5,6 tetrahydro 1H imid- 5） For selected examples, see: (a) Navarre, L.; Darses, S.; Genet, J. ─ P. ─ ─ ─ ─ ─ ─ ─ ─ Angew. Chem. Int. Ed. 2004, 43, 719. (b) Frost, C. G.; Penrose, S. D.; azo[1,2 ─ a]imidazole (1): The crude free triamine 4d (200 g) was Lambshead, K.; Raithby, P. R.; Warren, J. E.; Gleave, R. Org. Lett. dissolved in nitromethane (5 L). Thiophosgene (146 g, 1.25 2007, 9, 2119. (c) Nishimura, T.; Hirabayashi, S.; Yasuhara, Y.; equiv.) and triethylamine (246 g, 2.5 equiv.) were added to the Hayashi, T. J. Am. Chem. Soc. 2006, 128, 2556. (d) Navarre, L.; mixture slowly, then the whole was reuxed at 110 for 2 h. Martinez, R.; Genet, J. ─ P.; Darses, S. J. Am. Chem. Soc. 2008, 130, ℃ 6159. The reaction mixture was cooled to room temperature. Acetic 6） For selected examples, see: (a) Sibi, M. P.; Asano, Y.; Sausker, J. B. acid (234 g, 4 equiv.) and MeI (277 g, 2 equiv.) were added, Angew. Chem. Int. Ed. 2001, 40, 1293. (b) Sibi, M. P.; Sausker, J. B. J. then the mixture was reuxed at 110 ℃ for 3 h then left stirring Am. Chem. Soc. 2002, 124, 984. (c) Sadow, A. D.; Togni, A. J. Am. Chem. Soc. 2005, 127, 17012. (d) Emori, E.; Arai, T.; Sasai, H.; at room temperature overnight. CH 2Cl 2 (1 L) was added to Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043. (e) Nishide, K.; dilute the reaction mixture and the solvent was removed under Ohsugi, S.; Shiraki, H.; Tamakita, H.; Node, M. Org. Lett. 2001, 3, reduced pressure. The residue was diluted with water, and 3121. (f) Poisson, T.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. hydrochloric acid was added until the pH was 3. The mixture 2010, 132, 7890. 7） Pracejus, H.; Wilcke, F. W.; Hanemann, K. J. Prakt. Chem. 1977, 319, was extracted with DCM (500 mL×3) to remove impurities. 219. The aqueous phase was basi ed to pH 11 with sodium hydrox- 8） Li, B. J.; Jiang, M. Liu, L.; Chen, Y. C.; Ding, L. S.; Wu, Y. Synlett ide. It was then extracted with DCM (500 mL×3), and the 2005, 603. combined extracts were dried and concentrated to give the 9） (a) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (b) Wang, B.; Wu, F.; Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. guanidine 1 as the free amine (a pale yellow solid, 120 g, 60% 2007, 129, 768. 1 yield from IV). H NMR (400 MHz, CDCl 3, ppm): δ 0.95 (s, 10） Dai, X., Nakai, T., Romero, J. A. C.; Fu, G. C. Angew. Chem. Int. Ed. 18H), 3.25 (dd, J=9.0, 6.8 Hz, 2H), 3.41 (t, J=9.0 Hz, 2H), 2007, 46, 4367. 11） (a) Ye, W.; Xu, J.; Tan, C. T.; Tan, C. H. Tetrahedron Lett. 2005, 46, 4.12 (dd, J 9.0, 6.8 Hz, 2H), 6.23 (s, 2H). ─ ─ = 6875. (b) Ye, W.; Leow, D.; Goh, S. L. M.; Tan, C. ─ T.; Chian, C. ─ H.; Tan, C. H. Tetrahedron Lett. 2006, 47, 1007. (c) Shen, J.; Nguyen, T. 6． Conclusion ─ T.; Goh, Y. ─ P.; Ye, W.; Fu, X.; Su, J.; Tan, C. ─ H. J. Am. Chem. Soc. We have shown that the chiral bicyclic guanidine can act as 2006, 128, 13692. (d) Ye, W.; Jiang, Z.; Zhao, Y.; Goh, S. L. M.; Leow, D.; Soh, Y. ─ T.; Tan, C. ─ H. Adv. Synth. Catal. 2007, 349, 2454. (e) a Brønsted base catalyst in enantioselective protonation reac- Jiang, Z.; Zhang, Y.; Ye, W.; Tan, C. ─ H. Tetrahedron Lett. 2007, 48, tions. Strategies utilized included conjugate addition ─ enanti- 51. (f) Fu, X.; Jiang, Z.; Tan, C. ─ H. Chem. Commun. 2007, 47, 5058. oselective protonation and asymmetric isomerization, which (g) Leow, D.; Lin, S.; Chittimalla, S. K.; Fu, X.; Tan, C. ─ H. Angew. Chem. Int. Ed. 2008, 47, 5641. (h) Jiang, Z.; Ye, W.; Tan, C. ─ H. Adv. generate chiral products in high enantioselectivities. Related Synth. Catal. 2008, 350, 2345. (i) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; reactions catalyzed by other Brønsted base catalysts were also Lee, R.; Yang, Y.; Huang, K. ─ W.; Wong, M. W.; Tan, C. ─ H. Angew. reported. In addition, we also reported the rst enantiomeric Chem. Int. Ed. 2009, 48, 3627. (j) Liu, H.; Leow, D.; Huang, K. ─ W.; Tan, C. H. J. Am. Chem. Soc. 2009, 131, 7212. (k) Lin, S.; Leow, D.; enrichment reaction of racemic compounds through H ─ D ─ Huang, K. ─ W.; Tan, C. ─ H. Chem. Asian J. 2009, 4, 1741. (l) Jiang, Z.; exchange. Yang, Y.; Pan, Y.; Zhao, Y.; Liu, H.; Tan, C. ─ H. Chem. Eur. J. 2009, 15, 4925. (m) Jiang, Z.; Pan, Y.; Zhao, Y.; Ma, T.; Lee, R.; Yang, Y.; Acknowledgments Huang, K. ─ W.; Wong, M. W.; Tan, C. ─ H. Angew. Chem. Int. Ed. 2009, We would like to acknowledge the tremendous contribu- 48, 3627. (n) Liu, L.; Feng, W.; Kee, C. W.; Leow, D.; Loh, W. ─ T.; Tan, C. ─ H. Adv. Synth. Catal. 2010, 352, 3373. (o) Wang, J.; Liu, H.; Fan, tions of every member of the TCH family who was involved in Y.; Yang, Y.; Jiang, Z.; Tan, C. ─ H. Chem. Eur. J. 2010, 16, 12534. (p) the guanidine project. It is through the hard work and creativ- Pan, Y.; Zhao, Y.; Ma, T.; Yang, Y.; Liu, H.; Jiang, Z.; Tan, C. ─ H. ity of these members that the secrets of the guanidine chemi- Chem. Eur. J. 2010, 16, 779. (q) Fu X.; Tan, C. ─ H. Chem. Commun. 2011, 47, 8210. (q) Cho, B.; Tan, C. ─ H.; Wah, M. ─ W. Org. Biomol. stry were revealed. National University of Singapore, Nanyang Chem. 2011, 9, 4550. (r) Zhang, Y.; Kee, C. W.; Lee, R.; Fu, X.; Soh, J. ＊ Technological University, A Star and GlaxoSmithKline are Y. T.; Loh, E. M. F.; Huang, K. ─ W.; Tan, C. ─ H. Chem. Commun. gratefully acknowledged for funding of this research. 2011, 47, 3897. (s) Zhao, Y.; Pan, Y.; Liu, H.; Yang, Y.; Jiang, Z.; Huang, K. ─ W.; Tan, C. ─ H. Chem. Eur. J. 2011, 17, 3571. (t) Wang, J.; Chen, J.; Kee, C. W.; Tan, C. ─ H. Angew. Chem. 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有機合成化学71-11＿05論文_Wang.indd 42 2013/10/21 11:45:25 1196. PROFILE 16） (a) Ma, S. Acc. Chem. Res. 2003, 36, 701. (b) Ma, S. Chem. Rev. 2005, 105, 2829. Chao Wang obtained his B.S. degree in 17） (a) Jung, M. E.; Node, M.; Puger, R. W.; Lyster, M. A.; Lowe, J. A., chemistry in the University of Science and III J. Org. Chem. 1982, 47, 1150. (b) Jung, M. E.; Lowe, J. A., III; Technology of China in 2007 and completed Lyster, M. A.; Node, M.; Puger, R. W.; Brown, R. W. Tetrahedron his Ph.D. studies there under the supervision 1984, 40, 4751. (c) Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett. of Prof Liu ─ Zhu Gong in 2012. He is now a 1989, 30, 6559. (d) Ma, D.; Yu, Y.; Lu, X. J. Org. Chem. 1989, 54, research fellow in Prof Tan’s group where he 1105. focuses on asymmetric phase ─ transfer cataly- 18） Oku, M.; Arai, S.; Katayama, K.; Shioiri, T. Synlett 2000, 493. sis. 19） (a) Oppolzer, W.; Chapuis, C.; Dupuis, D.; Guo, M. Helv. Chim. Acta 1985, 68, 2100. (b) Jung, M. E.; Nishimura, N. Org. Lett. 2001, 3, 2113. 20） (a) Ma, S.; Wu, S. Tetrahedron Lett. 2001, 42, 4075. (b) Ma, S.; Wu, S. Cindy Mei Ting Goh is currently a nal ─ year Chem. Commun. 2001, 441. (c) Font, J.; Gracia, A.; de March, P. Tet- undergraduate pursuing Bachelor of Science rahedron Lett. 1990, 31, 5517. (d) Shingu, K.; Hagishita, S. Nakagawa, in Chemistry and Biological Chemistry in M. Tetrahedron Lett. 1967, 8, 4371. Nanyang Technological University. She 21） Wu, Y.; Singh, R. P.; Deng, L. J. Am. Chem. Soc. 2011, 133, 12458. joined Prof Tan’s research group in May 22） Lee, J. H.; Deng, L. J. Am. Chem. Soc. 2012, 134, 18209. 2013. 23） For review, see: Han, J.; Sorochinsky, A. E.; Ono, T.; Soloshonok, V. A. Curr. Org. Synth. 2011, 8, 281. 24） (a) Xiao X.; Xie, Y.; Su, C.; Liu, M.; Shi, Y. J. Am. Chem. Soc. 2011, Shihua Xiao is a Research Scientist of Rafes 133, 12914. (b) Xiao X.; Liu, M.; Rong, C.; Xue, F.; Li, S.; Xie, Y.; PharmaTech. He received his B.Sc. from Shi, Y. Org. Lett. 2012, 14, 5270. Chemistry at Jiangxi Science and Technology 25） For recent examples, see: (a) Soloshonok, V. A.; Yasumoto, M. J. Fluo- Normal University, China in 2009. He rine Chem. 2007, 128, 170. (b) Michaut, V.; Metz, F.; Paris, J. ─ M.; worked in Bellen Chemistry Co Ltd as Or- Plaquevent, J. ─ C. J. Fluorine Chem. 2007, 128, 500. ganic Synthesis Scientist between 2009 and 26） Wu, Y.; Deng, L. J. Am. Chem. Soc. 2012, 134, 14334. 2011. In 2012, He joined Rafes Pharma- Tech. His current work centers in organic catalysts.

Weiping Ye is the Chief Executive Of cer of Rafes PharmaTech in Guangdong, China. He received his B.Sc. in Chemistry and minor in Economics from Peking University in 2003. He obtained his Ph.D. degree in organic chemistry at National University of Singa- pore in 2007. He worked in GlaxoSmithKline as Chemist/Senior Chemist between 2006 and 2010. In 2010, He moved to P zer and assumed the role of API Manager for Global External Supply ─ Asia Region.

Choon Hong Tan received his B.Sc. (Hons) First C─lass from the National University of Singapore (NUS) in 1995. He graduated with a Ph.D. from the University of Cambridge in 1999. Following that, he was a postdoctoral fellow in the Department of Chemistry and Chemical Biology, Harvard University. Sub- sequently, he worked as a Research Associate in the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School before joining the Depart- ment of Chemistry, National University of Singapore as Assistant Professor in 2003. He was promoted to Associate Professor in 2010. He moved to Nanyang Technological Uni- versity as an Associate Professor in 2012. His current research interest is practical asymmetric catalysis.

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