186 Current Organic Synthesis, 2008, 5, 186-216 Asymmetric Epoxidation of Electron-Deficient Olefins David Díez*, Marta G. Núñez, Ana B. Antón, P. García, R.F. Moro, N.M. Garrido, Isidro S. Marcos, P. Basabe and Julio G. Urones Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, 37006 Salamanca, Spain Abstract: This paper focuses on the latest developments in asymmetric epoxidation of electron-deficient olefins since the review by Por- ter and Skidmore on chiral ligand-metal peroxide systems, polyamino acid catalysed and organocatalysed epoxidations. Particular atten- tion has been paid to the most recent advances using chiral pyrrolidines as organocatalysts. Key Words: Asymmetric epoxidation, electron deficient olefins, organocatalysis, dioxiranes, chiral ligand–metal peroxide systems, Juliá- Colonna epoxidation. Dedicated to Prof. M. Yus on the occasion of his 60th birthday. 1. INTRODUCTION years only two of them appear to have remained interesting among An excellent review on the asymmetric epoxidation of electron- synthetic organic chemists: the use of tartrates and BINOL 1 as deficient olefins was published in 2000 by Porter and Skidmore [1]. ligands (Fig. 1). Since then, there have been several important developments in this area, especially the use of chiral pyrrolidines as organocatalysts. This review is an update of the one by Porter and Skidmore. ROOC OH From the work of Weitz-Scheffer on epoxidation of electron- OH OH deficient carbonyl compounds [2] using alkaline H2O2, much pro- gress has been made towards the development of an asymmetric OH OH OH variant. The resulting enantiomerically enriched epoxy compounds ROOC can be easily transformed into many types of useful chiral com- pounds [3]. In the mid-1970s, phase-transfer catalysis was investi- gated by Wynberg et al. [4] in a biphasic Weitz-Scheffer epoxida- Tartrate tion using chiral ammonium salts derived from Cinchona alkaloids. derivatives (R)-BINOL, 1a (S)-BINOL, 1b In the early 1980s, Juliá and coworkers developed a new methodol- ogy for the asymmetric epoxidation of ,-unsaturated ketones Fig. (1). using polyamino acids which meant a breakthrough for this type of reactions [5]. Several methods for the asymmetric epoxidation of 2a. Alkyl Tartrate-Metal Peroxides electron deficient alkenes that use chiral ligand-metal peroxide Jackson et al. had previously established that treatment of (E)- systems have been reported [6]. Prof. Shibasaki et al. and Prof. chalcone 2 with a reagent prepared from lithium tert-butylperoxide Jackson et al. have described different catalyst systems based on and a stoichiometric amount of diethyl tartrate (DET) gave the cor- organometallic complexes with BINOL [7] and tartrate derivatives responding epoxide 3 in moderate yield and 62% ee, being essential [8] respectively. These processes allow the epoxidation of a wide a stoichiometric amount of lithium tert-butoxide for the reaction to range of electron-deficient olefins with high enantioselectivity. proceed (Scheme 1) [8]. Other methodologies developed for this reaction include the use of chiral alkyl hydroperoxides [9] and chiral dioxiranes [10]. Recently, the use of chiral pyrrolidines as organocatalysts has been reported BuLi (3.3 equivs.) t-BuOOH (2.2 equivs.) O as a new methodology for asymmetric epoxidation of electron- O O deficient olefins [11]. n-BuOH (1.1 equivs.) Ph Ph This review will not include methods that rely on structural Ph Ph features such as allylic alcohols for the asymmetric epoxidation of (+)-DET (1.1 equivs.) 3 an electron-deficient alkene [12]. Many other methods for the syn- 2 Dry toluene 62 % ee thesis of chiral epoxides from other substrates apart from electron 71-75% conv deficient alkenes can be found in an excellent review by Xia et al. covering homogeneous and heterogeneous catalytic asymmetric Bu2Mg (0.1 equivs.) O O O epoxidation [13]. t-BuOOH (1.1 equivs.) Ph Ph Ph Ph 2. CHIRAL LIGAND-METAL PEROXIDES SYSTEMS (+)-DET (0.11 equivs.) Several methods that rely on the use of a chiral ligand coordi- 2 Dry toluene 4 nated to the metal atom of a metal peroxide have been developed 94 % ee for the epoxidation of electron-deficient olefins. Many of these 85% conv systems were reviewed by Porter and Skidmore [1]. During the last Scheme 1. *Address correspondence to this author at the Departamento de Química In contrast, when the magnesium system was explored, it was Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, found that only a catalytic amount of base and chiral ligand were 37006 Salamanca, Spain; Tel: 34-923294474; Fax: 34-923294574; required to effect the epoxidation (Scheme 1). This reaction was E-mail: [email protected] 1570-1794/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Asymmetric Epoxidation of Electron-Deficient Olefins Current Organic Synthesis, 2008, Vol. 5, No. 3 187 more enantioselective, giving chalcone epoxide 4 in 94% ee and tert-butylhydroperoxide (prepared by extraction of commercial with the opposite absolute configuration to that obtained with the 70% aqueous tert-butylhydroperoxide into toluene, without azeo- lithium system using the same enantiomer of ligand [14,15]. In tropic distillation) gave similar results, making the work-up easier order to apply this methodology to aliphatic enones, Jackson added for large scale operations. When using “wet” tert-butylhydroper- powered activated 4Å molecular sieves to the system. The use of oxide, the ligand of choice was di-iso-propyl tartrate [15] and it was di-tert-butyl tartrate (Dt-BT) as ligand, magnesium ethoxide as base demonstrated that a combination of water and 4Å molecular sieves and the introduction of ultrasonication, increased the levels of con- was optimal for the process. The mechanism proposed by Jackson version and enantioselectivity up to 99% and 94% respectively [14, is depicted in Scheme 3. 15]. These authors also found that the addition of a small amount of ethanol could eliminate the need for ultrasonication, allowing a 2b. BINOL Systems substantial reduction in the amount of base required (Scheme 2). Probably the most general method for the catalytic asymmetric epoxidation of electron deficient olefins uses a combination of lan- thanide alkoxides and BINOL derivatives with alkyl hydroperox- 4Å molecular sieves O Bu Mg (0.1equivs.) O ides as oxygen source [7]. Shibasaki et al. have developed two 2 O types of catalyst systems for the asymmetric epoxidation of unsatu- t-BuOOH (1.1 equivs.) R R rated carbonyl compounds. One of them consists of complexes of R2 R1 2 1 (+)-DtBT (0.11 equivs.) general form LnM3[(R)-BINOL]3 (Ln=lanthanide, M=alkali metal) 71-93 % ee Dry toluene (5 in Fig. 2, where Ln=La) and the other one is alkali-metal-free (6 92-96% conv in Fig. 2). In both cases a complex between a lanthanide metal and BINOL is formed [16]. It was found that LaNa3[(R)-BINOL]3 (5 in 4Å molecular sieves O Fig. (2), when M=Na) complex afforded chalcone epoxide in 92% O (EtO)2Mg (0.24 equivs.) O yield and 83% ee with tert-butyl hydroperoxide (TBHP) as oxidant, t-BuOOH (1.1 equivs.) although it did not prove to be general for other enone substrates. R2 R1 R2 R1 On the contrary, the alkali-metal-free catalyst La-BINOL 6 (when (+)-DtBT (0.08 equivs.) 90-94 % ee Ln=La) gave the epoxidation reaction for a wider range of (E)- Dry toluene, sonication enones with excellent enantiomeric excesses when cumyl hydrop- 96-99% conv eroxide (CHP) was used as oxidant [7, 16]. 4Å molecular sieves The optimization of the reaction revealed that the optimum lanthanide metal depended on the substrate; lanthane was the best Bu2Mg (0.06 equivs.) O O O one for chalcone-type substrates, whereas ytterbium complexes t-BuOOH (1.1 equivs.) exhibited better catalytic activity for aliphatic substrates using R2 R1 R R TBHP as oxidant (Table 1). These latter complexes were used for 2 1 t (+)-D BT (0.08 equivs.) 91-96 % ee the epoxidation of (Z)-enones to the corresponding cis-epoxides EtOH (0.48 equivs.) 94-99% conv with high enantiomeric excess [16]. r.t. 1h catalyst formation Further development has been achieved by Inanaga and co- workers with the use of additives such as triphenylphosphine oxide Scheme 2. [17] or derivatives such as tris(4-fluorophenyl)phosphine oxide [18]. In this manner, the reaction time was shortened and the chiral Jackson et al. have studied the effect of adding a range of other lanthanum complex system was stabilised. Addition of Ph3As=O additives when using dibutylmagnesium as base. Addition of water was investigated by Shibasaki and it was found that the catalytic improved the results, whereas omission of the molecular sieves activity was increased even with reduced amounts of catalyst (Table completely inhibited the reaction. Interestingly, the use of “wet” O O Ot-Bu O Ot-Bu R2 O H t-BuOOH O H O H Mg H O Mg H O Ot-Bu O Ot-Bu O O R2 R1 O R1 OH + O O R2 R1 O O Ot-Bu Ot-Bu H H O H O O H O O Mg H Mg H R2 R2 O O Ot-Bu O Ot-Bu O O O O R1 R1 Scheme 3. Catalytic cycle proposed by Jackson for the asymmetric epoxidation of enones promoted by the alkyl-tartrate magnesium system. 188 Current Organic Synthesis, 2008, Vol. 5, No. 3 Díez et al. M * O OH OH O O * * La M OH OH O O O M * 1a 5 AsPh O 3 O O Ln Oi-Pr Ln O O Oi-Pr n 6 7 Fig. (2). Table 1. Enantioselective Epoxidation of ,-Unsaturated Ketones with Different BINOL Complexes O (R) catalyst (5%) O La-BINOL TBHP in decane (1.2 equivs.) O Yb-BINOL R R La-BINOL-Ph3P=O 1 2 R1 R2 MS 4Å, THF, rt La-BINOL-Ph3As=O a R1 R2 Method Yield (%) ee (%) A 93 91 B 99 81 Ph Ph C 99 96 D 99 96 A 85 85 o-MOM-C6H4Ph Ph D 91 95 C 89 93 t-Bu Ph D 95 94 A 55 88 B 82 93 i-Pr Ph C 67 96 D 72 95 A 83 94 B 92 94 Me Ph C 92 93 D 92 >99 A 91 88 Me CH2CH2Ph C 92 87 D 98 92 A 71 91 Me C5H11 D 89 95 a A: La-BINOL, see ref 21; B: Yb-BINOL, H2O (4.5 equivs.