Vol. 7, No. 9 Organocatalysis Features include: • Proline Analogs • MacMillan Imidazolidinone ™ L-Proline, the archetype OrganoCatalysts of modern asymmetric organocatalysts • Chiral Phosphoric Acids • Jacobsen Thioureas • Cinchona Alkaloids 2 Introduction Vol. 7 No. 9 Organocatalysis and its asymmetric variant have emerged as new and powerful tools in chemical synthesis. Hardly a day passes without a new method being published on Aldrich Chemical Co., Inc. the synthesis of new chiral building blocks or complex molecular structures in a few Sigma-Aldrich Corporation steps beginning with cheap, readily available starting materials. At Sigma-Aldrich, we 6000 N. Teutonia Ave. believe there is a need to provide our customers with the most extensive portfolio of Milwaukee, WI 53209, USA commercially available organocatalysts. In addition, we offer at the end of this ChemFiles a comprehensive list of dedicated books and review articles on organocatalysis. 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Aldrich is a member of the About Our Cover Sigma-Aldrich Group. © 2007 Sigma-Aldrich Co. The cover illustration depicts the proteinogenic amino acid L-proline. Labeled by Jacobsen as the “simplest enzyme”, L-proline is capable of effecting a variety of organocatalytic asymmetric transformations. sigma-aldrich.com 3 Proline Analogs O OH CH3 The first examples were reported in the mid-70s, when L-proline H CH3 CH3 Intermolecular was applied to Robinson annulation reactions. However, the big cross-aldol reaction potential of proline as an organocatalyst was discovered at the up to 97%ee beginning of the 21st century. O OH O NHAr H OBn OBn OH The bifunctional structure of the sole cyclic proteinogenic amino NO2 α-oxyaldehyde L Mannich reaction acid is a crucial factor. -proline contains both a nucleophilic dimerization up to >99%ee H secondary amino group and a carboxylic acid moiety functioning up to 98%ee O N as a Brønsted acid. This facilitates a highly pre-organized transition H OH L-Proline state during the reaction pathway, which results in exceptionally O CO2Bn N CO Bn Proline Analogs OPh H N 2 high enantioselectivities. H H NO2 As a small organic molecule, proline is available in both intermolecular enantiomeric forms, which is a definite advantage over enzymatic α-amination Michael reaction O 23%ee up to 96%ee O methods. Numerous proline-catalyzed reactions have been NHPh developed (Scheme 1).1 R1 R2 α-aminooxylation Stimulated by such a vast number of successful examples, many up to >99%ee research groups have developed synthetic proline analogs with Scheme 1 optimized properties. Some examples are presented here in more detail. CH3 CO H N 2 The catalytic asymmetric α-alkylation of aldehydes was described OHC I H OHC 10 mol% 2 Et N, CHCl by List. This transformation had been accomplished with the EtO2C 3 3 EtO2C EtO C -30°, 24 h EtO C help of covalently attached auxiliaries. In comparison to L-proline, 2 2 92%, 95%ee α-methyl-L-proline (17249) gives higher enantioselectivities and improved reaction rates (Scheme 2). Scheme 2 Organocatalytic cyclopropanation reactions were typically performed using catalyst-bound ylides. However, MacMillan CO2H O Me O O N Pr H Ph demonstrated that activation of olefin substrates using catalytic S + Me Ph Pr H CHCl3, r.t. (S)-(–)-indoline-2-carboxylic acid (346802) is a viable route for the CHO formation of highly enantioenriched cyclopropanes (Scheme 3).3 78%, 94%ee, 27:1 dr Prof. Karl Anker Jørgensen and his group have developed (R)- and Scheme 3 (S)-α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether (677019 and 677213 resp.), which serve O O as excellent chiral organocatalysts in the direct organocatalytic H R α-functionalization of aldehydes. In the field of asymmetric 82-85% synthesis this stereoselective functionalization certainly represents 92-95%ee an important breakthrough. Jørgensen’s diarylprolinol silylether O O reagents were shown to catalyze a variety of bond-forming S Br H H reactions such as C–C, C–N, C–O, C–S, and C–Hal in high yields R R 60-94% 71-74% 4 F3C and excellent levels of enantiocontrol (Scheme 4). 95-98%ee CF3 94-95%ee O CF3 Enders and co-workers have developed a chemo-, diastereo-, and + H N R enantioselective three-component domino reaction, accomplished H OTMS CF3 with proline-derived organocatalyst 677183 and low cost, simple R'O C starting materials, leading to tetra-substituted cyclohexene 2 NH O O F 5 N H carbaldehydes (Scheme 5). The four stereogenic centers are R'O2C H R R generated in three consecutive carbon–carbon bond formations, 79-8% 55-75% 90-97%ee PMP 91-97%ee i.e., Michael/Michael/aldol condensation with high diastereo- and NH O EtO complete enantiocontrol. Thus, this domino reaction opens up a H O R simple and flexible entry to polyfunctional cyclohexene building 79-84% 94-98%ee blocks. 8:1-12:1 dr References: (1) (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Scheme 4 Am. Chem. Soc. 2002, 124, 827. (b) α-Amination: List, B. J. Am. Chem. Soc. 2002, 124, 5656. (c) α-Aminoxylation: Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247. Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808; Ph Ph Bøgevig, A.; Sunden, H.; Córdova. A. Angew. Chem. Int. Ed. 2004, 43, 1109. (d) Michael N O H OTMS O R1 addition: List, B.; Pojarliev, P.; Martin, H. J. Org. Lett. 2001, 3, 2423. (e) α-Oxyaldehyde O 20 mol% H 1 + 2 NO2 + dimerization: Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. R R R3 H H toluene, 0° to r.t. R2 R3 Chem. Int. Ed. 2004, 43, 2152. (f) Cross-aldol reaction: Northrup, A. B.; MacMillan, D. W. NO2 C. J. Am. Chem. Soc. 2002, 124, 6798. (2) Vignola, N.; List, B. J. Am. Chem. Soc. 2003, 25-58% 125, 450. (3) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. d.r. 6.8:3.2 to 9.9: 0.1 de, ee >99% (4) (a) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.; Jørgensen, sigma-aldrich.com K. A. J. Am. Chem. Soc. 2005, 127, 18296. (b) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 1790. (c) Marigo, M.; Scheme 5 Jørgensen, K. A. α-Heteroatom Functionalization. In Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007; Chapter 2.2. (d) Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (e) Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964. (f) Carlone, A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. Angew. Chem. Int. Ed. 2007, 46, 4504. (g) Ibrahem, I.; Rios, R.; Vesely, J.; Hammar, P.; Eriksson, L.; Himo, F.; Córdova, A. Angew. Chem. Int. Ed. 2007, 46, 4507. (5) Enders, D.; Hüttl, M. R. M.; Grondal, C.; Raabe, G. Science 2006, 441, 861. Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact your local Sigma-Aldrich office, or visit safcglobal.com. 4 L-Proline, ≥99% (TLC) trans-3-Hydroxy-L-proline, ≥98.0% (NT) OH C5H9NO2