Enantioselective Organocatalytic Addition of Oxazolones to 1, 1‐Bis (phenylsulfonyl) ethylene: A Convenient Asymmetric Synthesis of Quaternary α‐Amino Acids

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/44614785 ChemInform Abstract: Enantioselective Organocatalytic Addition of Azlactones to Maleimides: A Highly Stereocontrolled... Article in Chemistry - A European Journal · August 2010 DOI: 10.1002/chem.201000239 · Source: PubMed CITATIONS READS 56 66 6 authors, including: Guillem Valero Albert Moyano 18 PUBLICATIONS 587 CITATIONS 306 PUBLICATIONS 6,232 CITATIONS University of Barcelona SEE PROFILE University of Barcelona SEE PROFILE Ramon Rios University of Southampton 196 PUBLICATIONS 4,547 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Organocatalysis View project Synthesis of Fluorinated Compounds View project All content following this page was uploaded by Albert Moyano on 28 December 2016. The user has requested enhancement of the downloaded file. FULL PAPER DOI: 10.1002/chem.201000239 Enantioselective Organocatalytic Addition of Azlactones to Maleimides: A Highly Stereocontrolled Entry to 2,2-Disubstituted-2H-oxazol-5-ones Andrea-Nekane R. Alba,[a] Guillem Valero,[a] Teresa Calbet,[b] Merc Font-Barda,[b] Albert Moyano,*[a] and Ramon Rios*[a] Dedicated to Professor JosØ Barluenga on the occasion of his 70th birthday Abstract: The first highly diastereo- and enantioselective organocatalytic synthesis of 2,2-disubstituted-2H-oxazol-5-ones is described. The addition of oxazolones to maleimides is promoted by bifunctional thiourea catalysts, which afford the corresponding 2,2-disubstituted-2H-oxazol-5-ones with total regio- and stereocontrol. Introduction The enantioselective construction of quaternary stereocenters is a challenging goal in organic synthesis and this topic has received considerable attention from the synthetic community.[1] In this context, the alkylation of azlactones (4Hoxazol-5-ones) has emerged as one of the most useful ways to build quaternary stereocenters, due to their high reactivity and easy transformation into quaternary a-substituted aamino acid derivatives.[2] In 2008, Jørgensen and co-workers reported the first asymmetric oxazolone addition to a,b-unsaturated aldehydes, catalyzed by chiral secondary amines, with excellent results.[3] Subsequently, Jørgensen and coworkers[4] and ourselves[5] almost simultaneously disclosed the tertiary-amine-catalyzed azlactone addition to nitrostyrenes, which proceeded with high diastereoselectivities. One of the most interesting points to emerge from both papers was the regioselectivity of the reaction, which was depen- [a] A.-N. R. Alba, G. Valero, Prof. Dr. A. Moyano, Dr. R. Rios+ Department of Organic Chemistry, Universitat de Barcelona Mart i Franqus 1-11, 08028 Barcelona (Spain) Fax: (+ 34) 933397878 E-mail: amoyano@ub.edu rios.ramon@icrea.cat [b] T. Calbet, M. Font-Barda Departament de Cristalografia, Mineralogia i Dipsits Minerals Universitat de Barcelona, Mart i Franqus s/n 08028 Barcelona (Spain) [+] ICREA Researcher at UB Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201000239. Chem. Eur. J. 2010, 00, 0 – 0 Keywords: maleimides · Michael addition · organocatalysis · oxazolones dent on the substitution pattern of the azlactone. When 2aryl-substituted azlactones were used only C-2 addition was observed, whereas the use of 2-tert-butylazlactones exclusively afforded the C-4-substituted regioisomer (Scheme 1). Scheme 1. Regioselectivity of the addition of azlactones to nitrostyrenes. However, it should be highlighted that the nature of the electrophile also plays an important role in the regiochemistry of the addition. As first demonstrated by Steglich et al.,[6] in several cases the regiochemistry is totally directed by the nature of electrophile. Thus, a,b-unsaturated aldehydes appear to give C-4-substituted azlactones independent of the nature of C-2 substituent.[3] Very recently, we have found that the addition of azlactones to 1,1-bis(phenylsulfonyl)ethene also takes place with complete C-4 regioselectivity (Scheme 2).[7] With these results in mind, and in the context of a research program devoted to the development of new asymmetric methodologies based on organocatalysis,[8] we decided to study the behavior of azlactones towards other electrophiles, such as maleimides. Maleimides have been used extensively in metal-mediated asymmetric synthesis as dieno-  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim &1& These are not the final page numbers! ÞÞ Scheme 2. Regioselectivity of the addition of azlactones to a,b-unsaturated aldehydes and vinyl sulfones. philes[9] or dipolarophiles[10] in cycloadditions, or as Michael acceptors.[11] Following the landmark 1989 paper of Riant and Kagan,[12] maleimides have been employed in enantioselective Diels–Alder cycloadditions with anthrones[13] and, more recently, in asymmetric Michael reactions with 1,3-dicarbonyl compounds,[14] aldehydes,[15] and 2-mercaptobenzaldehydes.[16] Their use in vinylogous Michael reactions with a,a-dicyanoolefins has also been reported.[17] To the best of our knowledge, the asymmetric conjugate addition of azlactones to maleimides had not yet been studied and should provide a practical route to synthetically and biologically important chiral a-succinimidates.[18] Results and Discussion Our initial investigations revealed that 4H-oxazol-5-one 1 a underwent a Et3N-catalyzed Michael addition to N-phenylmaleimide (2 a) in toluene at room temperature (Scheme 3) to afford compound 3 a as mixture of diastereomers (2.4:1 diastereomeric ratio (d.r.)) in 92 % isolated yield, with complete C-2 regioselectivity. Scheme 3. Addition of azlactone 1 a to N-phenylmaleimide (2 a). We turned our attention to an asymmetric version of the same reaction. To this end, we tested Takemotos thiourea catalyst (S,S)-I[19] in different solvents, with the intention to take advantage of the bifunctional nature of the catalyst to improve the diastereoselectivity of the process[7] (Table 1). To our delight, the reaction afforded optically active adduct 3 a (84:16 enantiomeric ratio (e.r.)) when run in toluene at room temperature, with excellent diastereoselectivity (20:1 d.r.) and total conversion after 1 h (Table 1, entry 1). When the reaction was performed at 20 8C both the diastereoselectivity (25:1 d.r.) and the enantioselectivity (94:6 e.r.) increased, although the reaction rate was appreciably reduced (Table 1, entry 7). When the reaction was run in ethyl acetate (Table 1, entry 3) both the diastereoselectivity and the &2& www.chemeurj.org enantioselectivity were reduced, whereas chloroform (Table 1, entry 2) provided results only marginally inferior to those obtained with toluene. When polar solvents ethanol and DMF were used, no reaction was observed (Table 1, entries 4 and 5). Table 1. Optimization of reaction conditions with Takemotos thiourea.[a] Entry Solvent Conversion (1 h) [%][b] 1 2 3 4 5 6 7 toluene CHCl3 AcOEt EtOH DMF toluene toluene 100 100 100 – – 100 20 d.r.[b] e.r.[c] RT RT RT RT RT 4 20 20:1 18:1 13:1 – – 25:1 25:1 84:16 82:12 71:29 – – 87:13 94:6 [a] Maleimide 2 a (1 equiv) was added to a mixture of 1 a (1.2 equiv) and catalyst I (10 mol %). [b] Determined by 1H NMR spectroscopy of the crude reaction mixture. [c] Major diastereomer e.r., determined by chiral HPLC. Next, we screened catalysts other than (S,S)-I, which included chiral thioureas and bases derived from Cinchona alkaloids, in toluene at room temperature (Table 2). The reaction was efficiently catalyzed by quinidine-derived thiourea II, although with reduced enantioselectivity (Table 2, entry 2 versus 1). Quinine-derived thiourea III also catalyzed the addition but, surprisingly, with a very low reaction rate (Table 2, entry 3). When chiral bases quinine (VII), quinidine (VIII), and Sharpless ligands IV–VI were used no reaction was observed (Table 2, entries 4–8). This shows that the hydrogen-bond-donating thiourea moiety is crucial in the catalysis of this new reaction (see Scheme 5 below). Once the reaction conditions were optimized with respect to catalyst (Takemotos thiourea I) and solvent (toluene), we performed a screening of substituted azlactones. The scope of the reaction with C-2-substituted valine-derived azlactones 1 a–d is summarized in Table 3. As previously noticed by Jørgensen and co-workers[3] and ourselves,[7] when fluorine atoms were located in positions 2,4 on the phenyl ring the enantioselectivities increased up to 95:5 e.r. in relation to entry 1, Table 3. It should be noted that when 2alkyl-substituted oxazolones were treated with maleimides in the presence of catalyst I, a 3.5:1 regioisomeric mixture of C-4 and C-2 adducts was obtained. The major C-4 ad-  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ÝÝ These are not the final page numbers! T [8C] Chem. Eur. J. 0000, 00, 0 – 0 Organocatalytic Addition of Azlactones to Maleimides FULL PAPER Table 2. Catalyst screening.[a] Table 4. C-4 substituent screening: Addition of 2-(2,4-difluorophenyl)azlactones to N-phenylmaleimide.[a] Entry Catalyst Conversion (14 h) [%][b] d.r.[b] e.r.[c] 1 2 3 4 5 6 7 8 ACHTUNGRE(S,S)-I II III ACHTUNGRE(DHQD)2AQN[f] (IV) ACHTUNGRE(DHQD)2PHAL[g] (V) ACHTUNGRE(DHQD)2PYR[h] (VI) VII VIII 100 100 < 10 0 0 0 0 0 20:1 20:1 n.d.[e] – – – – – 84:16 68:32 n.d. – – – – – [a] Maleimide 2 a (1 equiv) was added to a mixture of 1 a (1.2 equiv) and catalyst I (10 mol %) in toluene at RT [b] Determined by 1H NMR spectroscopy of the crude reaction mixture. [c] Major diastereomer e.r., determined by chiral HPLC. [d] After 24 h, traces of the product were detected by NMR analysis. [e] n.d. = none detected. [f] (DHQD)2AQN = hydroquinidine(anthraquinone-1,4-diyl) diether. [g] (DHQD)2PHAL = 1,4-bis(dihydroquinidinyl)-phthalazine. [h] (DHQD)2PYR = hydroquinidine-2,5diphenyl-4,6-pyrimidinediyl diether. Table 3. C-2 substituent screening: Addition of 2-aryl-4-isopropylazlactones to N-phenylmaleimide.[a] Entry R Compound Yield [%][b] d.r.[c] e.r.[d] 1 2 3 4 Me iBu iPr tBu 3g 3f 3c 3e 73 87 99 99 4.4:1 8:1 25:1 > 25:1 95:5 96:4 95:5 99.5:0.5 [a] Maleimide 2 a (1 equiv) was added to a mixture of 1 (1.2 equiv) and catalyst I (10 mol %) in toluene and stirred for 14 h at 20 8C. [b] Isolated yield after column chromatography. [c] Determined by 1H NMR spectroscopy of the crude reaction mixture. [d] Major diastereomer e.r., determined by chiral HPLC. chromatographic purification, the essentially stereoisomerically pure adduct 3 e (> 25:1 d.r. and 99.5:0.5 e.r.) was obtained in 99 % yield. Finally, we studied the scope of the reaction with maleimides 2 a–e with azlactones derived from tert-leucine (Table 5). In all cases, the reactions were very stereoselecTable 5. Reaction scope: Addition of 2-aryl-4-tert-butylazlactones to Naryl maleimides.[a] Entry [e] Entry Ar Compound Yield [%][b] 1 2 3 4 Ph 2,6-F2C6H3 2,4-F2C6H3 2-FC6H4 3a 3b 3c 3d 76 76 99 85 T [8C] d.r.[c] e.r.[d] 20 20 4 RT 20:1 20:1 25:1 20:1 94:6 92:8 95:5 84:16 [a] Maleimide 2 a (1 equiv) was added to a mixture of 1 (1.2 equiv) and catalyst I in toluene. [b] Isolated yield after column chromatography. [c] Determined by 1H NMR spectroscopy of the crude reaction mixture. [d] Major diastereomer e.r., determined by chiral HPLC. ducts were produced with low diastereoselectivities and with moderate enantioselectivities.[20] We retained the 2-(2,4-difluorophenyl) substituent in azlactones 1 e–g to investigate the effect of the C-4 alkyl substituent (Table 4). Both the yields and the enantiomeric purities were good in all instances. The diastereoselectivity of the process was clearly dependent on the a-branching degree of the C-4 alkyl substituent and increased along the series methyl < isobutyl < isopropyl < tert-butyl (Table 4, entries 1–4, respectively). This last example (reaction with tertleucine-derived azlactone 1 e) was remarkable in that, after Chem. Eur. J. 2010, 00, 0 – 0 1 2 3[f] 4 5 6 7 Ar R 3 Yield [%][b] d.r.[c] e.r.[d] 2,4-F2C6H3 2,4-F2C6H3 2-FC6H4 2,4-F2C6H3 2,4-F2C6H3 2,4-F2C6H3 Ph Ph 4-MeOC6H4 Ph 3-ClC6H4 4-CF3C6H4 6-ClC6H4 Ph 3e 3h 3i 3j 3k 3l 3m 99 84 85 62 92 94 95 > 25:1 > 25:1 > 25:1 > 25:1 > 25:1 > 25:1 > 25:1 99.5:0.5 97.5:2.5 96:4 96:4 97:3 98:2 96:4 [a] Maleimide 2 (1 equiv) was added to a mixture of 1 (1.2 equiv) and catalyst I (10 mol %) in toluene and stirred for 14 h at 4 8C. [b] Isolated yield after column chromatography. [c] Determined by 1H NMR spectroscopy of the crude reaction mixture. [d] Major diastereomer e.r., determined by chiral HPLC. [e] Reaction run at 20 8C. [f] Reaction run at RT. tive and afforded diastereomerically pure (> 25:1 d.r.) 2aryl-2-(3-succinimidyl)-2H-oxazol-5-ones of high enantiomeric purity (> 96:4 e.r.). It should be noted that product 3 e precipitated from the solution in toluene and as a result could be isolated in enantiopure form (only one enantiomer detected by HPLC) and in 99 % yield by simple filtration of the reaction mixture. The relative and absolute configuration of compound 3 n, obtained from the reaction of azlactone 1 i (derived from (S)-isoleucine) with N-phenylmaleimide (2 a) (Scheme 4), were ascertained by X-ray diffraction analysis of a single crystal of the major diastereomer (Figure 1).  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org &3& These are not the final page numbers! ÞÞ A. Moyano, R. Rios et al. and suitability for large-scale reactions for practical industrial preparations.[22] Experimental Section General procedure for azlactone addition to maleimides: In a small flask, oxazolone 1 a–i (0.30 mmol, 1.2 equiv), maleimide 2 a–e (0.25 mmol, 1.0 equiv), and catalyst I (0.025 mmol, 0.1 equiv) in toluene (1 mL) were stirred at the temperature described in Tables 3–5 or Scheme 4. The crude products 3 a–n were purified by flash column chromatography. Scheme 4. Reaction of azlactone 1 i with maleimide 2 a. Compound 3 a: The reaction was run with (R,R)-I. Colorless oil, 88 % (c = 0.7, CHCl3); 1H NMR enantiomeric excess (ee). [a]25 D = 20.5 (400 MHz, CDCl3, TMSint): d = 7.61–7.56 (m, 2 H), 7.47–7.42 (m, 5 H), 7.41–7.36 (m, 1 H), 7.20–7.15 (m, 2 H), 3.89 (dd, J = 9.7, 5.4 Hz, 1 H), 3.02 (h, J = 6.8 Hz, 1 H), 2.93 (dd, J = 18.6, 5.4 Hz, 1 H), 2.75 (dd, J = 18.6, 9.7 Hz, 1 H), 1.30 (d, J = 6.8 Hz, 3 H), 1.24 ppm (d, J = 6.8 Hz, 3 H); 13 C NMR (75 MHz, CDCl3): d = 173.5, 172.7, 171.6, 163.2, 136.4, 131.3, 130.0, 129.3, 129.2, 129.1, 129.0, 128.9, 126.4, 126.2, 125.9, 104.7, 47.6, 31.7, 29.7, 28.3, 19.3, 19.1 ppm; HRMS (ESI): m/z: calcd for C22H21N2O4 : 377.1496 [M+H] + ; found: 377.1487; HPLC (Chiralpak IC, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): retention times (tR) for major diastereomer = 17.8, 28.7 min. Figure 1. X-ray structure of 3 n.[21] Based on these data, we tentatively propose a bifunctional transition state in which the tertiary amine of the catalyst deprotonates the azlactone and the thiourea moiety activates the maleimide, as shown in Scheme 5. Scheme 5. Proposed transition state for azlactone addition to maleimides. Conclusion We have reported a new, organocatalytic, easily executed, and highly enantioselective entry to 2H-oxazol-5-ones with quaternary stereocenters. The addition of 4-alkyl-azlactones 1 to maleimides 2 is efficiently catalyzed by bifunctional thiourea–amine I (both enantiomers of which are commercially available) with complete C-2 regioselectivity and with good to excellent diastereoselectivity. The resulting adducts are obtained with good yields and enantioselectivities. The procedure presented herein has distinct advantages in terms of operational simplicity, environmentally friendly conditions, &4& www.chemeurj.org Compound 3 b: The reaction was run with (S,S)-I. Colorless oil, 84 % ee. 1 [a]25 D = + 10.0 (c = 1.0, CHCl3); H NMR (300 MHz, CDCl3, TMSint): d = 7.48–7.38 (m, 4 H), 7.23–7.20 (m, 2 H), 7.02–6.96 (m, 2 H), 4.41 (dd, J = 8.9, 6.0 Hz, 1 H), 3.03 (h, J = 6.7 Hz, 1 H), 2.97 (dd, J = 18.5, 9.7 Hz, 1 H), 2.89 (dd, J = 9.5, 7.2 Hz, 1 H), 1.29 (d, J = 6.9 Hz, 3 H), 1.23 ppm (d, J = 6.9 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 173.3, 172.6, 171.0, 163.4, 161.7 (d, J = 6.5 Hz), 159.2 (d, J = 7.3 Hz), 132.3, 132.2, 132.0, 131.3, 129.3, 129.2, 128.9, 128.9, 126.6, 126.2, 113.3 (d, J = 3.4 Hz), 113.0 (d, J = 2.7 Hz), 45.5, 31.5, 28.1, 19.1, 18.8 ppm; 19F NMR (376 MHz, CDCl3): d = 105.3 (m), 107.3 ppm (m); HRMS (ESI): m/z: calcd for C22H19F2N2O4 : 413.1307 [M+H] + ; found: 413.1305; HPLC (Chiralpak IC, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): tR for major diastereomer = 18.2, 30.0 min. Compound 3 c: The reaction was run with (R,R)-I. Colorless oil, 90 % ee. 1 [a]25 D = 17.0 (c = 2.1, CHCl3); H NMR (300 MHz. CDCl3, TMSint): d = 7.47–7.35 (m, 4 H), 7.20–7.16 (m, 2 H), 6.99–6.89 (m, 2 H), 4.28 (dd, J = 9.7, 5.6 Hz, 1 H), 3.05 (h, J = 6.8 Hz, 1 H), 2.86 (dd, J = 18.4, 9.7 Hz, 1 H), 2.72 (dd, J = 18.4, 5.6 Hz, 1 H), 1.31 (d, J = 6.8 Hz, 3 H), 1.24 ppm (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 173.3, 172.8, 172.5, 165.2 (d, J = 11.9 Hz), 163.0, 162.7 (d, J = 12.3 Hz), 161.8 (d, J = 12.7 Hz), 159.3 (d, J = 11.9 Hz), 131.2, 129.6 (dd, J = 10.0, 4.2 Hz), 129.2, 128.9, 126.2, 111.6 (dd, J = 21.1, 21.2 Hz), 105.8, 105.5, 105.3, 102.5 (d, J = 3.8 Hz), 44.9 (d, J = 4.6 Hz), 31.5, 28.4, 19.3, 19.0 ppm; 19F NMR (376 MHz. CDCl3): d = 105.3 (m), 106.9 ppm (m); HRMS (ESI): m/z: calcd for C22H19F2N2O4 : 413.1307 [M+H] + ; found: 413.1304; HPLC (Chiralpak IC, 1 mL min 1, hexane/iPrOH 75:25, 254 nm): tR major diastereomer = 13.3, 19.5 min. Compound 3 d: The reaction was run with (S,S)-I. Colorless oil, 67 % ee. 1 [a]25 D = 10.5 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.47–7.56 (m, 5 H), 7.26–7.17 (m, 4 H), 4.35 (dd, J = 9.4, 5.9 Hz, 1 H), 3.06 (h, J = 6.9 Hz, 1 H), 2.85 (dd, J = 18.6, 9.7 Hz, 1 H), 2.79 (dd, J = 18.2, 5.6 Hz, 1 H), 1.32 (d, J = 6.9 Hz, 3 H), 1.24 ppm (d, J = 6.8 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): d = 173.4, 172.9, 172.3, 163.1, 161.4, 158.9, 135.4 (d, J = 9.9 Hz), 132.1 (d, J = 8.8 Hz), 129.2, 128.9, 128.4 (d, J = 2.7 Hz), 126.5, 126.2, 124.5 (d, J = 4.2 Hz), 123.7 (d, J = 11.9 Hz), 116.9 (d, J = 116.9 Hz), 102.9 (d, J = 3.4 Hz), 44.9 (d, J = 4.9 Hz), 31.7, 28.4, 19.3, 19.1 ppm; 19F NMR (376 MHz, CDCl3): d = 111.4 ppm (t, J = 16.0 Hz); HRMS (ESI): m/z: calcd for C22H19FN2NaO4 : 417.1221 [M+Na] + ; found: 417.1222; HPLC (Chiralpak IA, 1 mL min 1, hexane/iPrOH 90:10, 254 nm): tR major diastereomer = 67.7, 70.5 min. Compound 3 e: The reaction was run with (R,R)-I. Colorless oil, 99 % ee. 1 [a]25 D = 13.8 (c = 1.1, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.48–7.37 (m, 4 H), 7.21–7.19 (m, 2 H), 6.99–6.91 (m, 2 H), 4.27 (dd, J = 9.7, 5.5 Hz, 1 H), 2.85 (dd, J = 18.3, 9.7 Hz, 1 H), 2.73 (dd, J = 18.4, 5.6 Hz, 1 H), 1.34 ppm (s, 9 H); 13C NMR (100 MHz, CDCl3): d = 173.8, 173.3,  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ÝÝ These are not the final page numbers! Chem. Eur. J. 0000, 00, 0 – 0 Organocatalytic Addition of Azlactones to Maleimides 172.7, 165.2 (d, J = 11.2 Hz), 162.7 (d, J = 11.9 Hz), 161.9, 159.3 (d, J = 11.9 Hz), 134.2, 131.2, 129.6 (dd, J = 9.9, 4.2 Hz), 129.2, 129.1, 128.9, 126.4, 126.2, 111.6 (dd, J = 21.1, 3.5 Hz), 105.1 (dd, J = 25.3, 25.4 Hz), 101.2 (d, J = 4.2 Hz), 44.9 (d, J = 5.0 Hz), 35.0, 31.5, 26.8 ppm; 19F NMR (376 MHz, CDCl3): d = 106.3 (m), 107.8 ppm (m); HRMS (ESI): m/z: calcd for C23H24F2N3O4 : 444.1729 [M+NH4] + ; found: 444.1731; HPLC (Chiralpak IB, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer = 26.7, 28.6 min. Compound 3 f: The reaction was run with (S,S)-I. Colorless foam, 1 H NMR (400 MHz, CDCl3, 92 % ee. [a]25 D = + 9.5 (c = 1.1, CHCl3); TMSint): d = 7.50–7.35 (m, 4 H), 7.21–7.16 (m, 2 H), 7.00–6.89 (m, 2 H), 4.29 (dd, J = 9.7, 5.8 Hz, 1 H), 2.86 (dd, J = 18.3, 9.7 Hz, 1 H), 2.73 (dd, J = 18.3, 5.8 Hz, 1 H), 2.59–2.54 (m, 2 H), 2.21 (h, J = 6.7 Hz, 1 H), 0.99 (d, J = 6.7 Hz, 3 H), 0.96 ppm (d, J = 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 173.1, 172.8, 167.7, 165.2 (d, J = 11.9 Hz), 163.7, 162.8, 162.6, 161.7 (d, J = 12.3 Hz), 159.2 (d, J = 12.3 Hz), 134.2, 131.2, 129.5 (dd, J = 4.2, 10.0 Hz), 129.2, 129.1, 128.9, 128.8, 127.9, 126.4, 126.2, 126.0, 111.7 (dd, J = 21.5, 3.4 Hz), 105.8, 105.5, 105.3, 103.0 (d, J = 3.8 Hz), 44.9 (d, J = 4.2 Hz), 36.8, 31.4, 26.0, 22.6, 22.5 ppm; 19F NMR (376 MHz, CDCl3): d = 105.4 (m, 1 F), 106.8 ppm (m, 1 F); HRMS (ESI): m/z: calcd for C23H21F2N2O4 : 427.1464 [M+H] + ; found: 427.1464; HPLC (Chiralpak IA, 1 mL min 1, hexane/iPrOH 90:10, 254 nm): tR major diastereomer = 25.8, 27.3 min. Compound 3 g: The reaction was run with (R,R)-I. Colorless foam, 1 H NMR (400 MHz, CDCl3, 90 % ee. [a]25 D = 12.4 (c = 1.5, CHCl3); TMSint): d = 7.48–7.36 (m, 4 H), 7.21–7.15 (m, 2 H), 7.00–6.88 (m, 2 H), 4.27 (dd, J = 9.7, 5.6 Hz, 1 H), 2.86 (dd, J = 18.3, 9.7 Hz, 1 H), 2.67 (dd, J = 18.3, 5.6 Hz, 1 H), 2.37 ppm (s, 3 H); 13C NMR (100 MHz, CDCl3): d = 173.1, 165.1, 163.7, 162.8, 161.8, 159.2, 131.2, 129.7, 129.2, 128.9, 126.2, 119.8, 111.8, 105.5, 45.0, 31.4, 14.1 ppm; 19F NMR (376 MHz, CDCl3): d = 105.4 (m), 107.1 ppm (m); HRMS (ESI): m/z: calcd for C20H14F2KN2O4 : 423.0553 [M+K] + ; found: 423.0553; HPLC (Chiralpak IA, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer = 16.1, 17.6 min. Compound 3 h: The reaction was run with (R,R)-I. Yellow oil, 95 % ee. 1 [a]25 D = 12.0 (c = 1.1, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.42–7.36 (m, 1 H), 7.12–7.08 (m, 2 H), 6.99–6.91 (m, 4 H), 4.26 (dd, J = 9.7, 5.6 Hz, 1 H), 3.81 (s, 3 H), 2.84 (dd, J = 18.4, 9.7 Hz, 1 H), 2.71 (dd, J = 18.4, 5.4 Hz, 1 H), 1.34 ppm (s, 9 H); 13C NMR (75 MHz, CDCl3): d = 173.8, 173.6, 173.0, 165.6 (d, J = 11.6 Hz), 162.0, 159.7, 158.9 (d, J = 11.8 Hz), 129.5 (dd, J = 10.1, 4.5 Hz), 127.4, 123.8, 120.1 (dd, J = 12.1, 4.0 Hz), 114.6, 111.6 (dd, J = 21.1, 3.8 Hz), 105.5 (dd, J = 25.9, 26.0 Hz), 101.2 (d, J = 4.0 Hz), 55.5, 44.9 (d, J = 4.5 Hz), 35.0, 31.4, 26.9 ppm; 19 F NMR (376 MHz, CDCl3): d = 106.3 (m), 107.8 ppm (m); HRMS (ESI): m/z: calcd for C24H26F2N3O5 : 474.1835 [M+NH4] + ; found: 474.1837; HPLC (Chiralpak IA, 1 mL min 1, hexane/iPrOH 90:10, 254 nm): tR major diastereomer = 29.0, 36.4 min. Compound 3 i: The reaction was run with (R,R)-I. Colorless oil, 84 % ee. 1 [a]25 D = 20.1 (c = 1.5, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.47–7.37 (m, 5 H), 7.23–7.17 (m, 4 H), 4.33 (dd, J = 9.3 Hz, 5.8 Hz, 1 H), 2.85 (dd, J = 18.3, 9.3 Hz, 1 H), 2.78 (dd, J = 18.7, 5.9 Hz, 1 H), 1.35 ppm (s, 9 H); 13C NMR (100 MHz, CDCl3): d = 173.6, 173.5, 172.9, 162.0, 161.4, 158.9, 132.1 (d, J = 9.9 Hz), 131.3, 129.2, 128.8, 128.4 (d, J = 2.3 Hz), 126.5, 125.2, 124.5 (d, J = 3.4 Hz), 123.7 (d, J = 11.5 Hz), 116.9 (d, J = 21.8 Hz), 101.7 (d, J = 3.4 Hz), 44.9 (d, J = 4.9 Hz), 34.9, 31.7, 26.9 ppm; 19F NMR (376 MHz, CDCl3): d = 111.5 ppm (m); HRMS (ESI): m/z: calcd for C23H22FN2O4 : 409.1558 [M+H] + ; found: 409.1564; HPLC (Chiralpak IA, 1 mL min 1, hexane/iPrOH 95:5, 254 nm): tR major diastereomer = 65.5, 69.6 min. Compound 3 j: The reaction was run with (R,R)-I. Colorless oil, 92 % ee. 1 [a]25 D = 7.5 (c = 0.4, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.41–7.36 (m, 3 H), 7.25–7.24 (m, 1 H), 7.14–7.12 (m, 1 H), 6.99–6.91 (m, 2 H), 4.28 (dd, J = 9.7, 5.6 Hz, 1 H), 2.86 (dd, J = 18.5, 9.8 Hz, 1 H), 2.73 (dd, J = 18.5, 5.5 Hz, 1 H), 1.35 ppm (s, 9 H); 13C NMR (100 MHz, CDCl3): d = 173.9, 173.6, 172.8, 172.5, 172.3, 161.8, 134.7, 132.2, 130.2, 129.5 (dd, J = 8.4, 4.2 Hz), 129.2 (d, J = 5.6 Hz), 129.1, 126.5, 124.3, 111.7 (d, J = 21 Hz), 105.6 (dd, J = 26.6, 26.7 Hz), 101.1 (d, J = 8 Hz), 44.9, 35.0, 31.4, 26.8 ppm; 19F NMR (376 MHz, CDCl3): d = 105.4 (m), 107.1 ppm Chem. Eur. J. 2010, 00, 0 – 0 FULL PAPER (m); HRMS (ESI): m/z: calcd for C23H20ClF2N2O4 : 461.1074 [M+H] + ; found: 461.1073; HPLC (Chiralpak IB, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer = 11.7, 12.2 min. Compound 3 k: The reaction was run with (R,R)-I. Colorless oil, 94 % ee. 1 [a]25 D = 6.6 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.75–7.70 (m, 2 H), 7.42–7.35 (m, 3 H), 7.00–6.90 (m, 2 H), 4.30 (dd, J = 9.7, 5.5 Hz, 1 H), 2.89 (dd, J = 18.5, 9.7 Hz, 1 H), 2.74 (dd, J = 18.5, 5.5 Hz, 1 H), 1.33 ppm (s, 9 H); 13C NMR (100 MHz, CDCl3): d = 173.9, 172.7, 172.3, 165.3 (d, J = 11.9 Hz), 162.8 (d, J = 11.9 Hz), 161.9, 161.9, 159.3, 134.3, 130.7 (d, J = 33.7 Hz), 129.5 (dd, J = 9.5, 3.4 Hz), 126.4, 126.3, 120.0, 111.75 (dd, J = 21.1, 2.7 Hz), 105.8, 105.6, 105.3, 101.1 (d, J = 3.1 Hz), 45.0 (d, J = 4.2 Hz), 35.0, 31.5, 26.9 ppm; 19F NMR (376 MHz, CDCl3): d = 62.4 (s, 3 F), 105.2 (m, 1 F), 107.3 ppm (m, 1 F); HRMS (ESI): m/z: calcd for C24H20F5N2O4 : 495.1338 [M+H] + ; found: 495.1337; HPLC (Chiralpak IB, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer = 8.7, 14.7 min. Compound 3 l: The reaction was run with (R,R)-I. Colorless oil, 96 % ee. 1 [a]25 D = 8.6 (c = 1.4, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.45–7.35 (m, 3 H), 7.20–7.14 (m, 2 H), 7.00–6.90 (m, 2 H), 4.27 (dd, J = 9.7, 5.6 Hz, 1 H), 2.86 (dd, J = 18.5, 9.7 Hz, 1 H), 2.71 (dd, J = 18.5, 5.6 Hz, 1 H), 1.33 ppm (s, 9 H); 13C NMR (100 MHz, CDCl3): d = 173.9, 173.0, 172.5, 165.3 (d, J = 11.9 Hz), 162.7 (d, J = 12.7 Hz), 161.0, 159.3 (d, J = 12.3 Hz), 134.7, 129.4, 127.4, 119.9 (d, J = 11.1 Hz), 111.8, 111.6, 105.8, 105.6, 105.3, 101.2, 44.9, 35.0, 31.5, 26.9 ppm; 19F NMR (376 MHz, CDCl3): d = 105.3 (m), 107.0 ppm (m); HRMS (ESI): m/z: calcd for C23H20ClF2N2O4 : 461.1074 [M+H] + ; found: 461.1072; HPLC (Chiralpak IB, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer = 9.2, 17.2 min. Compound 3 m: The reaction was run with (R,R)-I. Colorless foam, 1 H NMR (300 MHz, CDCl3, 92 % ee. [a]25 D = 12.6 (c = 0.9, CHCl3); TMSint): d = 7.61–7.56 (m, 2 H), 7.50–7.38 (m, 6 H), 7.21–7.14 (m, 2 H), 3.87 (dd, J = 9.7, 5.2 Hz, 1 H), 2.93 (dd, J = 18.6, 5.3 Hz, 1 H), 2.74 (dd, J = 18.6, 9.7 Hz, 1 H), 1.33 ppm (s, 9 H); 13C NMR (75 MHz, CDCl3): d = 173.5, 172.9, 172.7, 162.1, 136.5, 134.0, 129.9, 129.2, 129.0, 128.8, 126.4, 103.5, 47.6, 34.9, 31.7, 26.9 ppm; HRMS (ESI): m/z: calcd for C23H23N2O4 : 391.1652 [M+H] + ; found: 391.1653; HPLC (Chiralpak IB, 1 mL min 1, hexane/iPrOH 80:20, 254 nm): tR major diastereomer = 9.9, 26.4 min. Compound 3 n: The reaction was run with (S,S)-I. White solid, 10:1 d.r. 1 [a]25 D = + 24.4 (c = 1.9, CHCl3); H NMR (400 MHz, CDCl3, TMSint): d = 7.60–7.55 (m, 2 H), 7.46–7.41 (m, 5 H), 7.40–7.35 (m, 1 H), 7.19–7.15 (m, 2 H), 3.91 (dd, J = 9.7, 5.5 Hz, 1 H), 2.93 (dd, J = 18.5, 5.5 Hz, 1 H), 2.87– 2.10 (m, 1 H), 2.75 (dd, J = 18.5, 9.7 Hz, 1 H), 1.89–1.77 (m, 1 H), 1.55– 1.45 (m, 1 H), 1.26 (d, J = 6.9 Hz, 3 H), 0.89 ppm (t, J = 7.5 Hz, 3 H); 13 C NMR (100 MHz, CDCl3): d = 173.5, 172.7, 170.9, 163.3, 136.5, 131.3, 129.8, 129.1, 129.0, 128.8, 126.4, 126.2, 104.8, 47.4, 35.0, 31.7, 26.6, 16.5, 11.6 ppm; HRMS (ESI): m/z: calcd for C23H23N2O4 : 391.1652 [M+H] + ; found: 391.1651. Acknowledgements We thank the Spanish Ministry of Science and Innovation (MICINN) for financial support (Project AYA2009-13920-C02-02). A.N.R.A is also grateful to MICINN for a Predoctoral fellowship. [1] For reviews on the asymmetric construction of quaternary stereocenters, see a) C. J. Douglas, L. E. Overman, Proc. Natl. Acad. Sci. 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The major diastereomer of this compound was isolated in 35 % yield after column chromatography and with a 85:15 e.r. CCDC-767697 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. After submission of this work, addition of oxazolones to a,b-unsaturated acylphosphonates was reported: H. Jiang, M. W. Paixao, D. Monge, K. A. Jørgensen, J. Am. Chem. Soc. 2010, 132, 2775.  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ÝÝ These are not the final page numbers! Received: January 27, 2010 Published online: && &&, 2010 Chem. Eur. J. 0000, 00, 0 – 0 Organocatalytic Addition of Azlactones to Maleimides FULL PAPER Asymmetric Organocatalysis A.-N. R. Alba, G. Valero, T. Calbet, M. Font-Bardía, A. Moyano,* R. Rios* . . . . . . . . . . . . . . . . . . . . . . . . &&&&—&&&& Thio-E-urea-KA! The first highly diastereo- and enantioselective organocatalytic synthesis of 2,2-disubstituted2H-oxazol-5-ones is described. The addition of oxazolones to maleimides Chem. Eur. J. 2010, 00, 0 – 0 is promoted by bifunctional thiourea catalysts, which afford the corresponding 2,2-disubstituted-2H-oxazol-5-ones with total regio- and stereocontrol (see scheme).  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Enantioselective Organocatalytic Addition of Azlactones to Maleimides: A Highly Stereocontrolled Entry to 2,2-Disubstituted-2H-oxazol-5-ones www.chemeurj.org &7& These are not the final page numbers! ÞÞ View publication stats