The Design of Novel, Synthetically Useful (Thio)urea-Based Organocatalysts

Abstract

Selected recent developments in the area of (thio)urea-mediated organocatalysis from our laboratory are summarised.

1 Introduction and Background

2 Catalysis with Achiral (Thio)ureas

2.1 The Baylis-Hillman Reaction

2.2 The Corey-Chaykovsky Reaction

2.3 Organocatalytic Reduction of Ketones

2.4 Ring Opening of Epoxides

3 Catalysis with Chiral (Thio)ureas

3.1 Modified Cinchona Alkaloid Derivatives

3.1.1 Asymmetric Michael Addition

3.1.2 Asymmetric Nitroolefin Cyclopropanation

3.1.3 meso-Anhydride Desymmetrisation

3.1.4 Dynamic Kinetic Resolution of Azlactones

3.2 Friedel-Crafts-type Reactions: Axially Chiral Thioureas

4 Summary

Key words

organocatalysis - Michael additions - asymmetric synthesis - nitroalkenes - sulfonium ions

References

• For selected recent reviews dealing with organocatalysis, see:
• 1a Alcaide B. Almendros P. Angew. Chem. Int. Ed.  2008,  47:  4632 
• 1b Yu X. Wang W. Org. Biomol. Chem.  2008,  6:  2037 
• 1c Dondoni A. Massi A. Angew. Chem. Int. Ed.  2008,  47:  4638 
• 1d Connon SJ. Org. Biomol. Chem.  2007,  5:  3407 
• 1e Ting A. Schaus SE. Eur. J. Org. Chem.  2007,  5797 
• 1f Lelais G. MacMillan DWC. In Frontiers in Asymmetric Catalysis   Mikami K. Lautens M. Wiley; Hoboken: 2007. 
• 1g Almaşi D. Alonso DA. Nájera C. Tetrahedron: Asymmetry  2007,  18:  299 
• 1h de Figueiredo RM. Christmann M. Eur. J. Org. Chem.  2007,  2575 
• 1i Tsogoeva SB. Eur. J. Org. Chem.  2007,  1701 
• 1j Mukherjee S. Yang JW. Hoffmann S. List B. Chem. Rev.  2007,  107:  5471 
• 1k Erkkilä A. Majander I. Pihko PM. Chem. Rev.  2007,  107:  5416 
• 1l Gaunt MJ. Johansson CCC. Chem. Rev.  2007,  107:  5596 
• 1m Enders D. Niemeier O. Henseler A. Chem. Rev.  2007,  107:  5606 
• 1n Atodiresi I. Schiffers I. Bolm C. Chem. Rev.  2007,  107:  5683 
• 1o Doyle AG. Jacobsen EN. Chem. Rev.  2007,  107:  5713 
• 1p McGarrigle EM. Myers EL. Illa O. Shaw MA. Riches SL. Aggarwal VK. Chem. Rev.  2007,  107:  5841 
• 1q Wurz RP. Chem. Rev.  2007,  107:  5570 
• 1r Connon SJ. Angew. Chem. Int. Ed.  2006,  45:  3909 
• 1s List B. Chem. Commun.  2006,  819 
• 1t Taylor MS. Jacobsen EN. Angew. Chem. Int. Ed.  2006,  45:  1520 
• 1u Akiyama T. Itoh J. Fuchibe K. Adv. Synth. Catal.  2006,  348:  999 
• 1v Connon SJ. Lett. Org. Chem.  2006,  3:  333 
• 1w Gaunt MJ. Johansson CCC. McNally A. Vo NT. Drug Discovery Today  2007,  12:  8 
• For selected reviews of (thio)urea-based organocatalysis, see:
• 2a Connon SJ. Chem. Commun.  2008,  2499 
• 2b Connon SJ. Chem. Eur. J.  2006,  12:  5418 
• 2c Takemoto Y. Org. Biomol. Chem.  2005,  3:  4299 
• 2d Schreiner PR. Chem. Soc. Rev.  2003,  32:  289 
• 3 Hine J. Ahn K. Gallucci JC. Linden S.-M. J. Am. Chem. Soc.  1984,  106:  7980 
• 4 Hine J. Linden S.-M. Kanagasabapathy VM. J. Am. Chem. Soc.  1985,  107:  1082 
• 5 Hine J. Linden S.-M. Kanagasabapathy VM. J. Org. Chem.  1985,  50:  5096 
• For further work on the same topic, see:
• 6a Hine J. Hahn S. Miles DE. Ahn K. J. Org. Chem.  1985,  50:  5092 
• 6b Hine J. Hahn S. Miles DE. J. Org. Chem.  1986,  51:  577 
• 6c Hine J. Ahn K. J. Org. Chem.  1987,  52:  2083 
• 6d Hine J. Ahn K. J. Org. Chem.  1987,  52:  2089 
• 7 Kelly TR. Meghani P. Ekkundi VS. Tetrahedron Lett.  1990,  31:  3381 
• 8a Etter MC. Panunto TW. J. Am. Chem. Soc.  1988,  110:  5896 
• 8b Etter MC. Urbañczyk-Lipkowska Z. Zia-Ebrahimi M. Panunto TW. J. Am. Chem. Soc.  1990,  112:  8415 
• 9 Previously, Tel and Engberts had obtained a crystal structure of an unstable N,N′-bis(α-tosylbenzyl)urea-acetone hydrogen-bonded adduct; see: Tel RM. Engberts JBFN. J. Chem. Soc., Perkin Trans. 2  1976,  483 
• For further general references, see:
• 10a Etter MC. Acc. Chem. Res.  1990,  23:  120 
• 10b Etter MC. J. Phys. Chem.  1991,  95:  4601 
• 10c Kelly TR. Kim MH. J. Am. Chem. Soc.  1994,  116:  7072 
• 11 Curran DP. Kuo LH. J. Org. Chem.  1994,  59:  3259 
• 12 Curran DP. Kuo LH. Tetrahedron Lett.  1995,  36:  6647 
• 13 Sigman MS. Jacobsen EN. J. Am. Chem. Soc.  1998,  120:  4901 
• 14a Sigman MS. Vachal P. Jacobsen EN. Angew. Chem. Int. Ed.  2000,  39:  1279 
• 14b Su JT. Vachal P. Jacobsen EN. Adv. Synth. Catal.  2001,  343:  197 
• 14c Vachal P. Jacobsen EN. Org. Lett.  2000,  2:  867 
• 14d Vachal P. Jacobsen EN. J. Am. Chem. Soc.  2002,  124:  10012 
• 15 Schreiner PR. Wittkopp A. Org. Lett.  2002,  4:  217 
• 16 Schreiner PR. Wittkopp A. Chem. Eur. J.  2003,  9:  407 
• 17 March J. Advanced Organic Chemistry   4th ed.:  Wiley-Interscience; New York: 1992. 
• 18 Baylis AB, and Hillman MED. inventors; Ger. Offen.  2155113.  ; US Patent 3743669; Chem. Abstr. 1972, 77, 34174q
• For selected reviews, see:
• 19a Masson G. Housseman C. Zhu J. Angew. Chem. Int. Ed.  2007,  46:  4614 
• 19b Basavaiah D. Rao AJ. Satyanarayana T. Chem. Rev.  2003,  103:  811 
• 19c Langer P. Angew. Chem. Int. Ed.  2000,  39:  3049 
• 20a Hill JS. Issacs NS. J. Phys. Org. Chem.  1990,  3:  285 
• 20b Bode ML. Kaye PT. Tetrahedron Lett.  1991,  32:  5611 
• 21a Price KE. Broadwater SJ. Jung HM. McQuade DT. Org. Lett.  2005,  7:  147 
• 21b Price KE. Broadwater SJ. Walker BJ. McQuade DT. J. Org. Chem.  2005,  70:  3980 
• 22 Aggarwal VK. Fulford SY. Lloyd-Jones GC. Angew. Chem. Int. Ed.  2005,  44:  1706 
• 23 This mechanistic rationale was partially supported by a study on the aza-Baylis-Hillman reaction from Leitner’s group, which found rate-limiting elimination in the absence of protic derivatives but not in the presence of the same (although, significantly, without observable autocatalysis); see: Buskens P. Klankermeyer J. Leitner W. J. Am. Chem. Soc.  2005,  127:  16762 
• We later observed the same relationship between catalyst basicity (all other things being approximately equal) and reactivity in the amine-catalysed hydroalkoxylation of Michael acceptors; see:
• 24a Faltin C. Fleming EM. Connon SJ. J. Org. Chem.  2004,  69:  6496 
• 24b Murtagh JE. McCooey SH. Connon SJ. Chem. Commun.  2005,  227 
• For examples, see:
• 25a Hamann BC. Branda NR. Rebek JR. Tetrahedron Lett.  1993,  34:  6837 
• 25b Smith PJ. Reddington MV. Wilcox CS. Tetrahedron Lett.  1992,  33:  6085 
• 25c Wilcox CS. Kim E.-I. Romano D. Kuo LH. Burt AL. Curran DP. Tetrahedron  1995,  51:  621 
• 25d Scheerder J. Engbersen JFJ. Casnati A. Ungaro R. Reinhoudt DN. J. Org. Chem.  1995,  60:  6448 
• 25e Nishizawa S. Kato R. Hayashita T. Teramae N. Anal. Sci.  1998,  14:  595 
• 25f Nam KC. Kang SO. Ko SW. Bull. Korean Chem. Soc.  1999,  20:  953 
• 26 Maher DJ. Connon SJ. Tetrahedron Lett.  2004,  45:  1301 
• 27 The pK _a (DMSO) values for N,N′-diphenylurea and N,N′-diphenylthiourea are 19.55 and 13.4, respectively; see: Bordwell FG. Acc. Chem. Res.  1988,  21:  456 
• 28a Ameer F. Drewes SE. Freese S. Kaye PT. Synth. Commun.  1988,  18:  495 
• 28b Drewes SE. Freese SD. Emslie ND. Roos GHP. Synth. Commun.  1988,  18:  1565 
• 29 Aggarwal VK. Emme I. Fulford SY. J. Org. Chem.  2003,  68:  692 
• 30a Johnson AW. LaCount RB. J. Am. Chem. Soc.  1961,  83:  417 
• 30b Corey EJ. Chaykovsky M. J. Am. Chem. Soc.  1962,  84:  867 
• 30c Franzen V. Driesen H.-E. Chem. Ber.  1963,  96:  1881 
• 30d Corey EJ. Chaykovsky M. J. Am. Chem. Soc.  1965,  87:  1353 
• For recent reviews, see reference 1p and:
• 31a Li A.-H. Dai L.-X. Aggarwal VK. Chem. Rev.  1997,  97:  2341 
• 31b Aggarwal VK. Richardson J. Chem. Commun.  2003,  2644 
• 31c Aggarwal VK. Winn CL. Acc. Chem. Res.  2004,  37:  611 
• For examples, see:
• 32a Merz A. Märk G. Angew. Chem., Int. Ed. Engl.  1973,  12:  845 
• 32b Bermand C. Comel A. Kirsch G. ARKIVOC  2000,  (ii):  128 
• 32c Borredon ME. Delmas M. Gaset A. Tetrahedron Lett.  1982,  23:  5283 
• 32d Borredon ME. Delmas M. Gaset A. Tetrahedron  1987,  43:  3945 
• 32e Bouda H. Borredon ME. Delmas M. Gaset A. Synth. Commun.  1987,  17:  503 
• 32f Lemini C. Ordonez M. Pérez-Flores J. Cruz-Almanza R. Synth. Commun.  1995,  25:  2695 
• 32g Ahmed A. Hoegenauer EK. Enev VS. Hanbauer M. Kaehlig H. Oehler E. Mulzer J. J. Org. Chem.  2003,  68:  3026 
• 34 For a recent study on the mechanism of the Corey-Chaykovsky reaction, see: Edwards DR. Montoya-Peleaz P. Crudden CM. Org. Lett.  2007,  9:  5481 
• 35 Kavanagh SA. Piccinini A. Fleming EM. Connon SJ. Org. Biomol. Chem.  2008,  6:  1339 
• For selected examples, see:
• 36a Ohnishi Y. Kagami M. Ohno A. J. Am. Chem. Soc.  1975,  97:  4766 
• 36b de Vries JG. Kellogg RM. J. Am. Chem. Soc.  1979,  101:  2759 
• 36c Ohno A. Ikeguchi M. Kimura T. Oka S. J. Am. Chem. Soc.  1979,  101:  7036 
• 36d Jouin P. Troostwijk CB. Kellogg RM. J. Am. Chem. Soc.  1981,  103:  2091 
• 36e Kanomata N. Nakata T. Angew. Chem., Int. Ed. Engl.  1997,  36:  1207 
• 36f Saito R. Naruse S. Takano K. Fukuda K. Katoh A. Inoue Y. Org. Lett.  2006,  8:  2067 
• For examples, see:
• 38a Wang JW. Hechavarria Fonseca MT. List B. Angew. Chem. Int. Ed.  2004,  43:  6660 
• 38b Wang JW. Hechavarria Fonseca MT. Vignola N. List B. Angew. Chem. Int. Ed.  2005,  44:  108 
• 38c Ouellet SG. Tuttle JB. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  32 
• 38d Wang JW. Hechavarria Fonseca MT. List B. J. Am. Chem. Soc.  2005,  127:  15036 
• 38e Huang Y. Walji AM. Larsen CH. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  15051 
• 38f Mayer S. List B. Angew. Chem. Int. Ed.  2006,  45:  4195 
• 39a Rueping M. Sugiono E. Theissmann T. Synlett  2005,  2367 
• 39b Rueping M. Sugiono E. Azap C. Theissmann T. Bolte M. Org. Lett.  2005,  7:  3781 
• 39c Hoffmann S. Seayad AM. List B. Angew. Chem. Int. Ed.  2005,  44:  7424 
• 39d Storer RI. Carrera DE. Ni Y. MacMillan DWC. J. Am. Chem. Soc.  2006,  128:  84 
• 39e Rueping M. Thiessmann T. Antonchick AP. Synlett  2006,  1071 
• 39f Rueping M. Antonchick AP. Thiessmann T. Angew. Chem. Int. Ed.  2006,  45:  3683 
• 40 Procuranti B. Connon SJ. Chem. Commun.  2007,  1421 
• For examples of metal(ion)-based catalysis of this reaction, see:
• 43a Kantam ML. Laha S. Yadav J. Sreedhar B. Tetrahedron Lett.  2006,  47:  6213 
• 43b Azizi M. Mehrazama S. Saidi MR. Can. J. Chem.  2006,  84:  800 
• 43c Bandini M. Fagioli M. Melloni A. Umani-Ronchi A. Adv. Synth. Catal.  2004,  346:  573 
• 43d For an example of this reaction in trifluoroethanol solvent, see: Bandini M. Cozzi PG. Melchiorre P. Umani-Ronchi A. J. Org. Chem.  2002,  67:  5386 
• 43e Westermaier M. Mayr H. Chem. Eur. J.  2008,  14:  1638 
• 44 Fleming EM. Quigley C. Rozas I. Connon SJ. J. Org. Chem.  2008,  73:  948 
• 45 Schreiner had previously demonstrated powerful cooperative catalysis between water and 6 in the addition of amines to epoxides; however, poor amine nucleophiles such as anilines were not used. Relatively nonselective additions of alcohols and thiols to an epoxide were also reported; see: Kleiner CM. Schreiner PR. Chem. Commun.  2006,  4315 
• 46 Recently, Schreiner and co-workers demonstrated impressive cooperative catalysis between 6 and mandelic acid in the alcoholysis of epoxides; see: Weil T. Kotke M. Kleiner CM. Schreiner PR. Org. Lett.  2008,  10:  1513 
• 47 Hiemstra H. Wynberg H. J. Am. Chem. Soc.  1981,  103:  417 
• 48 Okino T. Hoashi Y. Takemoto Y. J. Am. Chem. Soc.  2003,  125:  12672 
• 49 Okino T. Hoashi Y. Furukawa T. Xu X. Takemoto Y. J. Am. Chem. Soc.  2005,  127:  119 
• For examples of metal(ion)-based catalytic systems for this reaction, see:
• 50a Ji J. Barnes DM. Zhang J. King SA. Wittenberger SJ. Morton HE. J. Am. Chem. Soc.  1999,  121:  10215 
• 50b Barnes DM. Ji J. Fickes MG. Fitzgerald MA. King SA. Morton HE. Plagge FA. Preskill M. Wagaw SH. Wittenberger SJ. Zhang J. J. Am. Chem. Soc.  2002,  124:  13097 
• 50c Watanabe M. Ikagawa A. Wang H. Murata K. Ikariya T. J. Am. Chem. Soc.  2004,  126:  11148 
• 51 Deng and co-workers have also catalysed this reaction using 6′-demethylated cinchona alkaloid catalysts; see: Li H. Wang Y. Tang L. Deng L. J. Am. Chem. Soc.  2004,  126:  9906 
• 52 McCooey SH. Connon SJ. Angew. Chem. Int. Ed.  2005,  44:  6367 
• 53 It is worth noting that Pápai and co-workers have recently proposed an alternative mechanistic picture based on computational studies; see: Hamza A. Schubert G. Soós T. Pápai I. J. Am. Chem. Soc.  2006,  128:  13151 
• 54 Li B.-J. Jiang L. Liu M. Chen Y.-C. Ding L.-S. Wu Y. Synlett  2005,  603 
• 55 Vakulya B. Varga S. Csámpai A. Soós T. Org. Lett.  2005,  7:  1967 
• 56 Ye J. Dixon DJ. Hynes PS. Chem. Commun.  2005,  4481 
• 57a Wessjohann LA. Brandt W. Thiemann T. Chem. Rev.  2003,  103:  1625 
• 57b Donaldson WA. Tetrahedron  2001,  57:  8589 
• 57c Faust D. Angew. Chem. Int. Ed.  2001,  40:  2251 
• 58a Gnad F. Reiser O. Chem. Rev.  2003,  103:  1603 
• 58b Cativelia C. Diaz-de-Villegas MD. Tetrahedron: Asymmetry  2000,  11:  645 
• 58c De Pol S. Zorn C. Klein CD. Zerbe O. Reiser O. Angew. Chem. Int. Ed.  2004,  43:  511 
• 59 Aggarwal and co-workers have reported a Cu(acac)₂-catalysed cycloaddition of sulfonium ylides to Michael acceptors which gives good yields and stereoselectivities with enone substrates but poor yields and diastereoselectivities with nitroolefins; see: Aggarwal VK. Smith HW. Hynd G. Jones RVH. Fieldhouse R. Spey SE. J. Chem. Soc., Perkin Trans. 1  2000,  3267 
• Catalytic asymmetric Simmons-Smith-type cyclopropanation methodologies are best suited to electron-rich olefin substrates; see:
• 60a Lebel H. Marcoux F. Molinaro C. Charette AB. Chem. Rev.  2003,  103:  977 
• 60b Hartley RC. Caldwell ST. J. Chem. Soc., Perkin Trans. 1  2000,  477 
• 60c Lautens M. Klute W. Tam W. Chem. Rev.  1996,  96:  49 
• For representative references concerning the development of asymmetric Michael-based cyclopropanation methodologies, see:
• 61a Aggarwal VK. Smith HW. Jones RVH. Fieldhouse R. Chem. Commun.  1997,  1785 
• 61b Aggarwal VK. Alonso E. Fang G. Ferrara M. Hynd G. Porcelloni M. Angew. Chem. Int. Ed.  2001,  40:  1433 
• 61c Papageorgiou CD. Ley SV. Gaunt MJ. Angew. Chem. Int. Ed.  2003,  42:  828 
• 61d Bremeyer N. Smith SC. Ley SV. Gaunt MJ. Angew. Chem. Int. Ed.  2004,  43:  2681 
• 61e Papageorgiou CD. Cubillo de Dios MA. Ley SV. Gaunt MJ. Angew. Chem. Int. Ed.  2004,  43:  4641 
• 61f Kunz RK. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  3240 
• 61g Deng X.-M. Cai P. Ye S. Sun X.-L. Liao W.-W. Li K. Tang Y. Wu Y.-D. Dai L.-X. J. Am. Chem. Soc.  2006,  128:  9730 
• 61h Aggarwal VK. Acc. Chem. Res.  2004,  37:  611 
• 62 McCooey SH. McCabe T. Connon SJ. J. Org. Chem.  2006,  71:  7494 
• 63 For a recent review of asymmetric cyclopropanation, see: Pellissier H. Tetrahedron  2008,  64:  7041 
• For reviews, see reference 1n and:
• 64a Wong C.-H. Whitesides GM. Enzymes in Synthetic Organic Chemistry   Elsevier; Oxford: 1994. 
• 64b Willis MC. J. Chem. Soc., Perkin Trans. 1  1999,  175 
• 64c Spivey AC. Andrews BI. Angew. Chem. Int. Ed.  2001,  40:  3131 
• 64d Chen Y. McDaid P. Deng L. Chem. Rev.  2003,  103:  2965 
• 64e Tian S.-K. Chen Y. Hang J. Tang L. McDaid P. Deng L. Acc. Chem. Res.  2004,  37:  621 
• 65a Bolm C. Gerlach A. Dinter CL. Synlett  1999,  195 
• 65b Bolm C. Schiffers I. Dinter CL. Gerlach A. J. Org. Chem.  2000,  65:  6984 
• 65c See also: Bolm C. Schiffers I. Atodiresei I. Hackenberger PR. Tetrahedron: Asymmetry  2003,  14:  3455 
• 65d Rodríguez B. Rantanen T. Bolm C. Angew. Chem. Int. Ed.  2006,  45:  6924 
• 66 Chen Y. Tian S.-K. Deng L. J. Am. Chem. Soc.  2000,  122:  9542 
• 67a Hiratake J. Yamamoto Y. Oda J. J. Chem. Soc., Chem. Commun.  1985,  1717 
• 67b Hiratake J. Inagaki M. Yamamoto Y. Oda J. J. Chem. Soc., Perkin Trans. 1  1987,  1053 
• 68 Mass spectroscopic evidence supporting a nucleophilic catalysis mechanism has also been reported. Thus, it should be noted that both mechanisms may operate simultaneously; see: Bigi F. Carloni S. Maggi R. Mazzacani A. Sartori G. Tanzi G. J. Mol. Catal. A: Chem.  2002,  182-183:  533 
• 69 Peschiulli A. Gun’ko Y. Connon SJ. J. Org. Chem.  2008,  73:  2454 
• 71 Very shortly after our paper, a similar study using higher catalyst loadings (10 mol%) was reported; see: Rho SH. Oh SH. Lee JW. Lee JY. Chin J. Song CE. Chem. Commun.  2008,  1208 
• 72a Faber K. Chem. Eur. J.  2001,  7:  5004 
• 72b Pellissier H. Tetrahedron  2003,  59:  8291 
• 73 De Jersey J. Zerner B. Biochemistry  1969,  8:  1967 
• 74a Berkessel A. Cleemann F. Mukherjee S. Müller TN. Lex J. Angew. Chem. Int. Ed.  2005,  44:  807 
• 74b Berkessel A. Mukherjee S. Cleemann F. Müller TN. Lex J. Chem. Commun.  2005,  1898 
• 74c Berkessel A. Mukherjee S. Müller TN. Cleemann F. Roland K. Brandenburg M. Neudörfl J.-M. Lex J. Org. Biomol. Chem.  2006,  4:  4319 
• 75 Peschiulli A. Quigley C. Tallon S. Gun’ko YK. Connon SJ. J. Org. Chem.  2008,  73:  6409 
• 76a Dawson PE. Muir TW. Clark-Lewis I. Kent SB. Science (Washington, D.C.)  1994,  266:  776 
• 76b Macmillan D. Angew. Chem. Int. Ed.  2006,  45:  7668 
• 77 Only one such protocol has been reported; see: Honjo T. Sano S. Shiro M. Nagao Y. Angew. Chem. Int. Ed.  2005,  44:  5838 
• For reviews, see:
• 78a Bandini M. Melloni A. Tommasi S. Umani-Ronchi A. Synlett  2005,  1199 
• 78b Bandini M. Melloni A. Umani-Ronchi A. Angew. Chem. Int. Ed.  2004,  43:  550 
• 78c Jørgensen KA. Synthesis  2003,  1117 
• 79a Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2001,  123:  4370 
• 79b Austin JF. MacMillan DWC.
  J. Am. Chem. Soc.  2002,  124:  1172 
• 81 Dessole G. Herrera RP. Ricci A. Synlett  2004,  2374 
• 82a For a related report, see: Herrera RP. Sgarzani V. Bernardi L. Ricci A. Angew. Chem. Int. Ed.  2005,  44:  6576 
• 82b Herrera RP. Monge D. Martín-Zamora E. Fernández R. Lassaletta JM. Org. Lett.  2007,  9:  3303 
• 83 Fleming EM. McCabe T. Connon SJ. Tetrahedron Lett.  2006,  47:  7037 
• 84 During the course of our work, Jørgensen and co-workers reported a non-(thio)urea-based catalyst for these reactions. Product enantioselectivity was of the same order as that found in our study; however, using their system, aliphatic substrates proved more difficult than their aromatic counterparts; see: Zhuang W. Hazell RG. Jørgensen KA. Org. Biomol. Chem.  2005,  3:  2566 

33

See reference [²7] for details.

37

For a recent review of this topic, see reference [¹d] .

41

This hypothesis is supported by the presence of the reduced form of BNA as the only heterocyclic species observable (by ^¹H NMR spectroscopy) in the reduction of benzoin by BNA (organic phase).

42

It is assumed that product inhibition is not problematic in the systems being studied. To ensure that this is the case, the stability of the product-catalyst complex should be calculated and compared with that of the corresponding catalyst-substrate complex.

70

A simple base wash, extraction, acidification and extraction sequence furnishes pure product.

80

For a recent review of iminium catalysis, see reference [¹k] .

85

For examples of the demonstrable s-cis,cis-conformational preference of(thio)ureas, see references [8] , [9] and [49] .