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Asymmetric Organocatalysis Vol. 6 No. 4 Synthetic Methods Asymmetric Organocatalysis Proline Analogs MacMillan Imidazolidinone OrganoCatalysts™ Cinchona Alkaloids TADDOLs Schaus MBH Catalyst Rovis Triazolium Catalyst MacMillan Imidazolidinone OrganoCatalysts™ sigma-aldrich.com Introduction The field of organocatalysis has recently gained much attention in the chemical research community.1 For most chemists, the term catalysis was commonly equated to transition metal- Vol. 6 No. 4 mediated reactions or to enzyme-aided biocatalysis. However, small organic molecules can also achieve remarkably selective and efficient transformations—as intense research efforts in Aldrich Chemical Co., Inc. this emerging area are proving. The commercial potential of organocatalysis in the manner Sigma-Aldrich Corporation described is immense. The applied catalysts are of low molecular weight, easy to synthesize, 6000 N. Teutonia Ave. chemically robust, and affordable. Additionally, the organocatalytic reactions are often carried out under “open-flask” conditions. Milwaukee, WI 53209, USA This edition of ChemFiles describes applications of our existing products in the field of organocatalysis as well as exciting new additions to our organocatalysis portfolio. At To Place Orders Sigma-Aldrich, we are committed to being your preferred supplier of organocatalysts. Please visit sigma-aldrich.com/organocatalysis for a comprehensive listing of products. If you Telephone 800-325-3010 (USA) cannot find an organocatalyst, we welcome your input and will use it to broaden our product FAX 800-325-5052 (USA) range even further. “Please Bother Us“ at dweibel@europe.sial.com with your suggestions! Customer & Technical Services Customer Inquiries 800-325-3010 Technical Service 800-231-8327 ™ Introduction Sigma-Aldrich’s New Web-Based SAFC 800-244-1173 Custom Synthesis 800-244-1173 Chemistry Seminars Flavors & Fragrances 800-227-4563 International 414-438-3850 Cheminars™ 24-Hour Emergency 414-438-3850 Web Site sigma-aldrich.com • Featuring the latest innovative chemical synthesis technologies Email aldrich@sial.com and products • Access directly via your desktop browser • Convenient navigation Subscriptions • Highly interactive To request your FREE subscription to ChemFiles, please contact us by: Phone: 800-325-3010 (USA) Mail: Attn: Marketing Communications Aldrich Chemical Co., Inc. Sigma-Aldrich Corporation P.O. Box 355 Milwaukee, WI 53201-9358 Email: sams-usa@sial.com International customers, please contact your local Sigma-Aldrich office. For worldwide contact information, please see back cover. ChemFiles are also available in PDF format on the Internet at sigma-aldrich.com/chemfiles. Aldrich and Fluka brand products are sold through Sigma-Aldrich, Inc. Sigma-Aldrich, Inc. warrants that To check out Sigma-Aldrich’s new Web-based chemistry its products conform to the information contained in seminar series, please visit sigma-aldrich.com/cheminars. this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product for its particular use. See reverse side of invoice or packing slip for additional terms and conditions of sale. About Our Cover The cover illustration depicts one of the chiral MacMillan Imidazolidinone OrganoCatalysts™. These compounds were successfully employed in numerous organocatalytic transformations such as 1,3-dipolar cycloadditions, Friedel–Crafts alkylations, a-chlorinations, and intramolecular Michael reactions. Particularly noteworthy, the first direct organocatalytic enantioselective ChemFiles is a publication of Aldrich Chemical Co., a-fluorination of aldehydes has been accomplished to afford a broad spectrum of highly Inc. Aldrich and Fluka are members of the Sigma- enantioenriched a-fluoro aldehydes, which are valuable synthons for medicinal agent synthesis. Aldrich Group. © 2006 Sigma-Aldrich Co. sigma-aldrich.com US $ 3 Proline Analogs H3C O H3C O Coined by Jacobsen2 as the “simplest enzyme,” L-proline is capable O of effecting a variety of catalytic asymmetric transformations. The OH O first examples were reported in the mid-70s, when L-proline was Wieland-Miescher Ketone applied to Robinson annulation reactions.3 However, the big potential 100%, 93% ee 83%, 71% ee of proline as an organocatalyst was discovered in the beginning of OH the 21st century. One explanation for such a delay might be that O O 3 1 R2 the scope of highly selective transformations was considered to be R R R1 2 H rather narrow, and the development of metal catalysts seemed more Product R O Substrate N promising. H OH L-Proline The bifunctional structure of the sole cyclic proteinogenic amino H acid is a crucial factor. L-proline contains both a nucleophilic O H O N N secondary amino group and a carboxylic acid moiety functioning R2 O OH R1 H as a Brønsted acid. This facilitates a highly pre-organized transition R1 3 2 Proline Analogs state during the reaction pathway, which results in exceptionally high R OH Iminium ion R adduct enantioselectivities (Scheme 1).4 Iminium intermediate Moreover, as a small organic molecule, proline is available in both enantiomeric forms, which is a definite advantage over enzymatic H H O methods. Numerous proline-catalyzed reactions have been developed H O H N (Scheme ).5 O N H OH O H R1 R1 Stimulated by such a vast number of successful examples, many 3 R H R2 R2 Enamine intermediate research groups have developed synthetic proline analogs with O List−Houk optimized properties (see: ChemFiles Vol. 5 No. 12, Tools for Drug 3 transition state R H Discovery). Some examples will be presented here in more detail. Electrophile Scheme 1 The catalytic asymmetric a-alkylation of aldehydes was recently described by List.6 To date, this transformation was usually O OH CH3 accomplished with the help of covalently attached auxiliaries. In H CH3 comparison to L-proline, a-methyl-L-proline (1749) gives higher CH3 enantioselectivities and improved reaction rates (Scheme 3). Intermolecular cross-aldol reaction up to 97% ee Organocatalytic cyclopropanation reactions were typically performed O OH 7 O NHAr using catalyst-bound ylides. However, MacMillan demonstrated H that activation of olefin substrates using catalytic (S)-(–)-indoline-2- H3C OBn OBn OH NO2 carboxylic acid (34680) is a viable route for the formation of highly a-oxyaldehyde 8 dimerization H Mannich reaction enantioenriched cyclopropanes (Scheme 4). O up to 98% ee up to >99% ee N Order: 1.800.325.3010 Technical Service: 1.800.231.8327 Aggarwal utilized protonated (S)-(–)-2-(diphenylmethyl)pyrrolidine H OH (55534) as an organocatalyst in a novel process for the enantio- L-Proline O CO2Bn 9 selective epoxidation of alkenes. Although the reaction proceeds O Ph N CO2Bn H H N under phase-transfer conditions (PTC), it was found that secondary NO2 H amines catalyzed the reaction at remarkably higher rates, implying that 55534 does not act only as a PTC. However, best results were intermolecular O Michael reaction O a-amination obtained with the chiral pyrrolidine bearing 1-naphthyl substituents 23% ee NHPh up to 96% ee (Scheme 5). R1 R2 a-aminooxylation up to >99% ee L-Proline, ReagentPlus™, ;99% Scheme 2 C5H9NO2 CH3 MW: 115.13 CO H N 2 CO2H H N [a] –84.7° ± 1°, c = 4 in water OHC I H OHC 10 mol % [147-85-3] Et N, CHCl EtO2C 3 3 EtO2C P0380-10MG 10 mg 12.00 EtO2C −30 °C, 24 h EtO2C 92%, 95% ee P0380-100G 100 g 52.00 Scheme 3 P0380-1KG 1 kg 356.50 P0380-5KG 5 kg 1,533.60 CO2H O CH3 O O N Pr L-Proline, BioChemika, ;99.0% NT H Ph S + H3C Ph Pr H C5H9NO2 CHCl3, rt CHO MW: 115.13 N CO2H 6 H 78%, 94% ee, 27:1 dr [a] –84.5° ± 1°, c = 5% in water Scheme 4 [147-85-3] 81710-10G 10 g 10.60 Ph 81710-50G 50 g 35.10 N Cl H2 Ph 81710-250G 250 g 118.00 10 mol % 2 eq. Oxone Ph Ph 10 eq. NaHCO3 0.5 eq. pyridine O MeCN:H2O = 95:5 46% ee Scheme 5 Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact SAFC™ at 1-800-44-1173 (USA), or visit www.safcglobal.com. 4 D-Proline, ;99% L-Pipecolic acid, puriss., ;99.0% NT C5H9NO2 C6H11NO2 MW: 115.13 N CO2H MW: 129.16 OH H N H [a] +85.0°, c = 4 in water [a]6 –26° ± 1°, c = 4% in water O [344-25-2] [3105-95-1] 858919-500MG 500 mg 25.80 80615-100MG 100 mg 62.20 858919-5G 5 g 104.50 80615-500MG 500 mg 264.50 D-Proline, puriss., ;99.0% NT D-Pipecolic acid, purum, ;99.0% NT C5H9NO2 C6H11NO2 MW: 115.13 N CO2H MW: 129.16 OH H N H [a]6 +85° ± 2°, c = 5% in water [a]6 +27° ± 1°, c = 1% in water O [344-25-2] [1723-00-8] 81705-1G 1 g 45.80 80617-100MG 100 mg 86.20 81705-5G 5 g 108.50 80617-500MG 500 mg 366.50 81705-25G 25 g 501.90 (S)-(–)--(Diphenylmethyl)pyrrolidine, 97% -Methyl-L-proline, purum, ;98.0% TLC a C17H19N C H NO 6 11 2 CH MW: 237.34 MW: 129.16 3 N N CO2H [a] –3.0°, c = 1% in chloroform H [a] –75° ± 2°, c = 1% in methanol H [119237-64-8] [42856-71-3] 17249-250MG 250 mg 115.00 552534-500MG 500 mg 98.70 17249-1G 1 g 321.50 Proline Proline Analogs (R)-(+)--(Diphenylmethyl)pyrrolidine, 97% (S)-(–)-Indoline -carboxylic acid, 99% C17H19N C9H9NO2 MW: 237.34 CO2H N MW: 163.17 N [a]6 +3.0°, c = 1% in chloroform H [a]6 –114° c = 1 in 1N HCl H [22348-31-8] [79815-20-6] 346802-1G 1 g 22.20 552542-1G 1 g 91.60 346802-5G 5 g 83.40 a,a-Diphenyl-L-prolinol, purum, ;99.0% HPLC (R)-(+)-Indoline -carboxylic acid 8 sum of enantiomers C9H9NO2 C17H19NO CO2H MW: 163.17 N MW: 253.34 H [a]6 +114° c = 1 in 1N HCl 6 [a] –69° ± 2°, c = 3% in chloroform N [98167-06-7] [112068-01-6] H OH 51266-500MG 500 mg 58.90 43182-1G 1 g 62.10 43182-5G 5 g 245.50 3,4-Dehydro-L-proline, BioChemika, ;99.0% TLC C5H7NO2 a,a-Diphenyl-D-prolinol, purum, ;99.0% HPLC
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