Science Vision www.sciencevision.org Science Vision www.sciencevision.org Science Vision www.sciencevision.org Science Vision www.sciencevision.org Science Vision 16 (3) July-September Research Review ISSN (print) 0975-6175 ISSN (online) 2229-6026 Organocatalysts: A powerful tool for asymmetric Michael addition K. Vanlaldinpuia1* and P. B. Lalthanpuii2 1Department of Chemistry, Pachhunga University College, Aizawl 796001, India 2Department of Zoology, Pachhunga University College, Aizawl 796001, India Received 18 August 2016 | Revised 24 August 2016 | Accepted 29 August 2016 ABSTRACT In recent years, asymmetric organocatalysis has emerged as powerful tools for the synthesis of a variety of chiral molecules. Ready availability of the catalysts, low toxicity, simple operational pro- cedures and mild reaction conditions associated with organocatalysis makes it an attractive method to synthesise diverse complex structures. Here, a short review on the development and applications of chiral organocatalysts for asymmetric Michael addition reactions has been de- scribed. Key words: Asymmetric reaction; organocatalysis; Michael addition. INTRODUCTION Z Michael reaction or Michael addition or con- X Z EWG + EWG jugate addition is one of the most important methods for the mild formation of C-C bonds.1 Y X Y It may be defined as the nucleophilic addition of X, Y, Z = R or EWG stabilized anions (e.g. carbanion, enolates, etc.) Z X Z EWG = COR, CO R.ECWNG, NO , etc + EWG Z 2 2 to an α, β-unsaturated carbonyl and relatedX com- Z EWG pounds.2 It was named after an American Ychem-+ EWG X Y ist Arthur Michael (1853-1942) who reportedY the X, Y, Z = R or EWG X Y reaction that bears his name in 1887.2,3 XE,W YG, Z= =CORR o,r CEOW2RG. CN, NO2, etc EWG = COR, CO2R. CN, NO2, etc Corresponding author: Vanlaldinpuia Scheme 1. Michael addition. Phone: : +91-9862086476 E-mail: [email protected] CC BY-SA 4.0 International 2016 123 Organocatalysts: A powerful tool for asymmetric Michael addition The work done by Arthur Michael in 1887, their claim was without merit. on the formation of a cyclopropane derivative by the reaction of diethyl 2,3-dibrompropionate with diethyl sodiomalonate (Scheme 2), was motivated by the work of Conrad and Guthzeit.4 Br COOEt + EtOOC COOEt COOEt + EtOOC COOEt Br Na Br Na 1 2 3 2 Conrad & Guthzeit 1884 E t O O C C O O E t Michael 1887 COOEt Br 4 EtOOC COOEt COOEt 5 Scheme 2. Experiments done by Conrad & Guthzeit in 1884 and Michael in 1887. EtOOC COOEt EtONa / EtOH CO Et + EtOOC COOEt Ph 2 COOEt When Michael treated 2-bromacrylic acid rt, 4 days Ph ester with sodiomalonic acid ester, he obtained EtOOC COOEt EtONa / EtOH the same product reported by ConradCO Et +& EGuth-tOOC COO Et 4 Ph 2 COOEt zeit and realized that this reaction could only rt, 4 days Ph work by assuming an addition reaction to the double bond of the acrylic acid.2b,3 He then con- Scheme 3. First example of Michael addition reaction firmed this postulation by reacting diethyl malo- in 1887. nate and ethyl ester of cinnamic acid obtaining the very first Michael adduct (Scheme 3).2 Soon The Michael addition benefits from mild re- after its publication, Claisen5 claimed priority of action conditions, high functional group toler- the discovery of the reaction. Claisen and Kom- ance, a large host of polymerizable monomers nenos6 both observed addition products to dou- and functional precursors as well as high conver- ble bonds as side-products earlier in 1883 while sions and favourable reaction rates.9a These fea- investigating condensation reactions of malonic tures make the Michael addition reaction an im- acid with aldehydes. However, after the Claisen- portant organic transformation and the resultant Komenos report, condensation-addition prod- compounds have been used in the synthesis of ucts like theirs were also shown to formed in the several natural products, and drug molecules, reaction of formaldehyde with diethyl malonate numerous emerging technologies including bio- by Perkin Jr.7 and in the reaction of benzalde- medical applications such as gene transfection, hyde with ethyl acetoacetate by Hantzsch.8 cell scaffolds, and tissue replace- Hence, according to biographer Tokoroyama,3 ments.10a,10b,10c,9b,11,12 124 Vanlaldinpuia and Lalthanpuii ORGANOCATALYSIS 93% ee. O O The term “organocatalysis” was given by 13 Ahrendt et al. to sum up a group of organic MeCN, 11 (3 - 47 mol%) N COOH compounds used as catalysts to promote various O H O 0 asymmetric transformations. It is a branch of O r.t. - 80 C 10 catalysis in which a reaction is mediated solely 9 11 by small organic molecules in sub-stoichiometric Yield = 99 % quantities.14 Before 1960, there wereO few exam- O ee = 93 % ples of asymmetric organocatalysis but all of MeCN, 11 (3 - 47 mol%) them gave low enantiomeric excess (less than 20 N COOH H 15 0 O %) and hence, have no syntheticO O values. But inr.t . - 80 C 16a,b 1960, Pracejus et. al. reported that the use of 10 9 11 cinchona alkaloid derivative (8) catalysed the Yield = 99 % addition of methanol to phenylmethylketene (6), ee = 93 % giving (-)-α-phenyl methylpropionate (7) with 74 % enantiomeric excess (ee). Scheme 5. L-Proline catalysed asymmetric Robinson annulations. O H O Despite theseO wonderfulN results, there was not much improvement in the field of organo- O O MeOH, 3 (1 %) catalysisO for almost thirty years. But, since the year 2000, there was an explosive growth in this o Toluene, -110 C field and the use Nof chiral primary and secon- dary amines, chiral aziridinium and oxaziridin- 6 7 ium salts, cinchona8 alkaloids, etc. as a catalysts Yield = 93 % became a powerful tool in asymmetric synthe- ee = 74 % sis.14d Recently, asymmetric catalysis has been classified into three fields in which organocataly- sis has been placed in between metal catalysis 18 O H and enzymatic transformation. O O N O O MeOH, 3 (1 %) O ASYMMETRIC MICHAEL ADDITION USING ORGANOCATALYSTS o Toluene, -110 C N Asymmetric organocatalytic Michael addi- 6 7 8 tion has attracted a great deal of interest in re- Yield = 93 % cent years due to its environmental friendliness ee = 74 % Scheme 4. Cinchona alkaloid catalysed asymmetric and the generation of multiple stereogenic cen- addition of methanol. tres in a single step. Since the pioneering works of List19 and Barbas,20 organocatalytic asymmet- Subsequently in 1970s, Hajos et. al.17 also ric Michael additions have been thoroughly in- 21 reported for the first time, the use of amino acid vestigated, and in doing so, some well- L-Proline 11 as a catalyst for highly enantioselec- designed thiourea organocatalysts, such as pri- tive Robinson annulations reaction giving up to mary and tertiary amine-thiourea based cata- 125 Organocatalysts: A powerful tool for asymmetric Michael addition Table 1. Comparison between three classes of asymmetric catalysis. Metal based catalysts Organocatalysts Enzymes Transition metal A particular carbon heteroatom Combination of hundreds of amino as the active centre. skeleton that gives individual acids; however, only some of them characteristics to the active site. are active in the catalytic sites. Expensive and moisture /oxygen Not harmful in small amounts and No toxicity at all. sensitive and give some problem in often allow mild reaction the purification process, as only conditions and simple working small amounts of metals procedures. contaminants is tolerated for pharmaceuticals products. The catalysts loadings are often The catalysts loadings are typically The catalysts loadings are low. very low (up to 1000000/1 in under 100/1 in Substrate/Catalyst. Substrate /Catalyst). Both the enantiomer can be Both the enantiomer can be Synthesis of both the enantiomers obtained. obtained. is difficult. lysts, proline and its derivatives, and many other to electrophilically activate the enone via hydro- amine based organocatalysts have been success- 19-22a gen-bond donation to the carbonyl oxygen. fully developed for this reaction. Other O O classes of catalysts most frequently used in O 12 (5 mol%), 4oC Ph asymmetric Michael additions are cinchona al- R2 12 = R1 + H R N OMe kaloids and their derivatives.23 In this review, H Catechol 2 H O R Ph different types of Michael addition reaction us- 1 ing different organocatalysts will be highlighted. O O O 12 (5 mol%), 4oC Ph Yield = Upto 87% R2 12 = ee = Upto 99% R1 + H R N OMe MICHAEL ADDITIONH OF C-NUCLEOPHILESCate chol 2 H O R Ph 1 Most of the organocatalysts catalysed Mi- Yield = Upto 87% chael addition of C-nucleophiles proceeds via ee = Upto 99% enamine or iminium ion intermediate. Many successes have been realised by applying organo- Scheme 6. Diphenylprolinol methyl ether-catalysed catalysts such as proline derivatives to highly Michael additions of aldehydes to simple enones. reactive Michael donors or acceptors, but Mi- chael additions of simple aldehydes to simple In the same year, Peelan et al.26 also reported enones have received little attention.24 In 2005, MacMillan imidazolidinone catalyst (13) cata- Chi and Gelmann25 reported that diphenylproli- lysed intermolecular aldehyde-enone Michael nol methyl ether (12) could catalysed intermo- addition reaction using catechol as an additive lecular Michael addition of simple aldehydes to (Scheme 7). relatively non-activated enones with enantiose- O O O lectivities up to 99% with catalyst loading of 1-5 O 13 (20 mol%) R N mol% (Scheme 6). Although some of the reac- R + 2 13 = R H 1 H R2 tions proceeded smoothly with only the chiral Catechol, 20 mol% Bn N O R R pyrrolidine as a catalyst, others required the use 1 H of catechol as a co-catalyst, which was believed Yield = Upto 86% ee = Upto 92% 126 Vanlaldinpuia and Lalthanpuii O O O Another important class of organocatalysts O 13 (20 mol%) N R2 13 = for intermolecular Michael addition of C- R1 + R H H R2 Bn nucleophiles is cinchona alkaloids and its deriva- O Catechol, 20 mol% N R R1 H tives.