Chiral salen catalysts

Figure 18 Heterogenized chiral salen catalyst on siliceous MCM-41 according to Kim (ref. 169).

Chiral (salen) Mn(III) complexes have been found to be highly enantioselective for the asymmetric epoxidation of conjugated cis-disubstituted and trisubstituted oleftns[10]. The increasing interest towards this reaction brought some authors to develop the heterogeneous chiral salen catalysts. However, to date three kinds of approach have been adopted for the immobilization of chiral salens (1) Chiral Mn salen complexes were supported on polymers[l 1], (2) The encapsulation of salen complex using ship-in-bottle method was... 

A somewhat different approach to catalyst separation has been devised by engineering the chiral salen catalyst to have built-in phase-transfer capability, as exemplified by the Mn(III) complex 10 <02TL2665>. Thus, enantioselective epoxidation of chromene derivatives (e.g. 11) in the presence of 2 mol% catalyst 10 under phase transfer conditions (methylene chloride and aqueous sodium hypochlorite) proceeded in excellent yield and very good ee s. The catalyst loading could be reduced to about 0.4% with only marginal loss of efficiency. 

Good to excellent enantioselectivity was achieved in the epoxidation of mainly cyclic olefins with the chiral salen-catalyst 52 immobilised in [C4Ciim][PF6], but selectivity deteriorated upon catalyst recycling, see Scheme 5.6.[48] Relative to molecular solvents, higher reaction rates were observed even under biphasic conditions when the epoxidation reaction was carried out in the presence of an ionic liquid. UV-VIS spectroscopic1341 and cyclovoltammetric[49] studies suggest that the commonly observed superior reaction rates are a reflection of the solvent s ability to stabilise the active metalla-oxo intermediate. 

Ring opening with milder but more selective reagents such as NEtj -SHF or KHFj/lS-crown-G proceeds significantly more slowly but it can be catalyzed by electrophilic transition metal complexes. With a chiral salen catalyst even enantio-selective synthesis of chiral fluorohydrins can be achieved [70]. This type of reaction is of enormous interest for enantioselective synthesis of fluoropharmaceutical compounds (Scheme 2.26). 

The efficiency of new unsymmetrical chiral salen ligands was examined in the asymmetric trimethylsilylcyanation of benzaldehyde. A very high level of enantioselectivity was attainable over chiral Ti(IV) salen complexes prepared from salicylaldehyde and 3,5-Di-/ert-butylsalicylaldehyde derivative as compared to the conventional salen catalyst. Enantiomeric excess of the corresponding reaction product was generally more than 70% over unsymmetric chiral salen catalysts. The chiral Titanium(IV) salen complexes immobilized on a mesoporous MCM-41 by multi grafting method showed a relatively high enantioselectivity for the addition of trimethylsilyl cyanide to the benzaldehyde. 

Many interesting reports on the epoxidation of alkcnes have appeared in the literature, particularly involving asymmetric methods. In this regard, the chiral salen catalysts (1 and 2) developed by Jacobsen and Katsuki <01C()C663> find frequent use, and convenient methods for their industrial preparation continue to be reported. For example, Jacobsen s catalyst (1, Rl = R2 = <-Bu X = Q) is now available in 75% overall yield from commercially available starting materials <01SC2913>. 

Chen, D., Guo, L., Kotti, S. R. S. S., Li, G. (2005). The first asymmetric catalytic halo aldol reaction of (3-iodo allenoates with aldehydes by using chiral salen catalyst. Tetrahedron Asymmetry, 16, 1757-1762. 

To date, a wide variety of structurally different chiral Mn(III)salen complexes have been prepared, of which only a handful have emerged as synthetically useful catalysts. By far the most widely used Mn(III)salen catalyst is the commercially available Jacobsen catalyst wherein R= -C4H8- and R = = i-Bu (Scheme 1.4.1). In... 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

Jacobsen subsequently reported a practical and efficient method for promoting the highly enantioselective addition of TMSN3 to meso-epoxides (Scheme 7.3) [4]. The chiral (salen)Cl-Cl catalyst 2 is available commercially and is bench-stable. Other practical advantages of the system include the mild reaction conditions, tolerance of some Lewis basic functional groups, catalyst recyclability (up to 10 times at 1 mol% with no loss in activity or enantioselectivity), and amenability to use under solvent-free conditions. Song later demonstrated that the reaction could be performed in room temperature ionic liquids, such as l-butyl-3-methylimidazo-lium salts. Extraction of the product mixture with hexane allowed catalyst recycling and product isolation without recourse to distillation (Scheme 7.4) [5]. 

Hou reported the use of a chiral (salen)titanium catalyst for the desymmetriza-tion of meso-epoxides with thiols (Scheme 7.14). The complex, fonned in situ... 

Ten years after Sharpless s discovery of the asymmetric epoxidation of allylic alcohols, Jacobsen and Katsuki independently reported asymmetric epoxidations of unfunctionalized olefins by use of chiral Mn-salen catalysts such as 9 (Scheme 9.3) [14, 15]. The reaction works best on (Z)-disubstituted alkenes, although several tri-and tetrasubstituted olefins have been successfully epoxidized [16]. The reaction often requires ligand optimization for each substrate for high enantioselectivity to be achieved. 

One way of overcoming these problems is by kinetic resolution of racemic epoxides. Jacobsen has been very successful in applying chiral Co-salen catalysts, such as 21, in the kinetic resolution of terminal epoxides (Scheme 9.18) [83]. One enantiomer of the epoxide is converted into the corresponding diol, whereas the other enantiomer can be recovered intact, usually with excellent ee. The strategy works for a variety of epoxides, including vinylepoxides. The major limitation of this strategy is that the maximum theoretical yield is 50%. 

Non-covalently Immobilized Catalysts Based on Chiral Salen Ligands. . 152... 

The hydrolytic kinetic resolution (HKR) of terminal epoxides using Co-salen catalysts provides a convenient route to the synthesis of enantioemiched chiral compounds by selectively converting one enantiomer of the racemic mixture (with a maximum 50% yield and 100% ee) (1-3). The use of water as the nucleophile makes this reaction straightforward to perform at a relatively low cost. The homogeneous Co(III) salen catalyst developed by Jacobsen s group has been shown to provide high... 

A chiral aluminum-salen catalyst gives good enantioselectivity in the addition of cyanide (from TMS-CN) to unsaturated acyl imides.338... 

Further efficient ligands for the epoxidation of alkenes have been reported by Pozzi, but using PhIO as the oxidant and pyridine V-oxide as an additive in FBS.[7, 51-53] Chiral (salen)Mn complexes have been synthesised, which are soluble in fluorous solvents and active in the epoxidation of a variety of alkenes. The catalysts were of the form shown in Figure 6.14. 

The addition of cyanide to imines, the Strecker reaction, constitutes an interesting strategy for the asymmetric synthesis of a-amino acid derivatives. Sigman and Jacobsen150 reported the first example of a metal-catalyzed enan-tioselective Strecker reaction using chiral salen Al(III) complexes 143 as the catalyst (see Scheme 2-59). 

Many efforts have been made to develop salen catalysts for the epoxidation of unfunctionalized olefins, and such work has been well documented.93 Very recently, Ito and Katsuki94 proposed that the ligand of the oxo salen species is not planar, but folded as shown in Figure 4-7 (R/ / H, R2 = H, L = achiral axial ligand). This folded chiral structure amplifies asymmetric induction by the Mn-salen complex. This transition state proposed by Ito and Katsuki is not compatible with the proposal by Palucki et al.95 that the salen ligands of oxo species are planar. 

Miyafuji and Katsuki95 reported the desymmetrization of meso-tetrahydrofuran derivatives via highly enantioselective C-H oxidation using Mn-salen catalysts. The optically active product lactols (up to 90% ee) are useful chiral building blocks for organic synthesis (Scheme 8-48). 

Although the Sharpless catalyst was extremely useful and efficient for allylic alcohols, the results with ordinary alkenes were very poor. Therefore the search for catalysts that would be enantioselective for non-alcoholic substrates continued. In 1990, the groups of Jacobsen and Katsuki reported on the enantioselective epoxidation of simple alkenes both using catalysts based on chiral manganese salen complexes [8,9], Since then the use of chiral salen complexes has been explored in a large number of reactions, which all utilise the Lewis acid character or the capacity of oxene, nitrene, or carbene transfer of the salen complexes (for a review see [10]). 

Langanke J, Leitner W (2008) Regulated Systems for Catalyst Immobilisation Based on Supercritical Carbon Dioxide. 23 91-108 Larock R (2005) Palladium-Catalyzed Annulation of Alkynes. 14 147-182 Larrow JF, Jacobsen EN (2004) Asymmetric Processes Catalyzed by Chiral (Salen)Metal Complexes 6 123-152... 

Soluble polymer-bound catalysts for epoxidation reactions have also been explored, with a complete study into the nature of the polymeric backbone performed by Janda [70]. Chiral (salen)-Mn complexes were appended to MeO-PEG, NCPS, Jan-daJeF and Merrifield resin via a glutarate spacer. It was found that for the Jacobsen epoxidation of ds-/ -mefhylstyrene, the enantioselectivities for each polymer-supported catalyst were comparable (86-90%) to commercially available Jacobsen catalyst (88%). Both soluble polymer-supported catalysts could be used twice before a decline in yield and enantioselectivity was observed. However, neither soluble polymer support proved as suitable as the insoluble JandaJel-supported (salen)-Mn complex for the epoxidation because residual impurities during precipitation and leaching of Mn from the complex, resulted in lowered yields. 

Figure 4. Structure of fluorous chiral Co(salen) catalysts 6-8.

Kim et al. [67] recently reported the synthesis of heterometallic chiral polymer (salen) Co-(Al, Ga, ln)Cl3 complexes 26-32 (Figure 10) and their use in the HKR of racemic epoxides. Polymeric salen catalysts showed very high reactivity and enantioselectivity at substantially lower catalyst loadings for the asymmetric ring opening of terminal epoxide to obtain the enantio-enriched products. The performance of catalysts is retained on multiple-use and do not suffer the problems of solubility and deactivation (Scheme 5). 

Kim and Park [71] reported multi-step synthesis of various unsymmetrical chiral salen Co(lll)(OAc) complexes co-valently bonded onto MCM-41 type mesoporous Al-Si material (39-44) (Figure 14). Authors developed a new approach of anchoring method where the reaction of a functionalized ligand, diformylphenol, was carried out with 3-aminopropyltrimethoxysilane modified Al-MCM-41. These supported catalysts were used in the HKR of racemic epichlorohydine, 1,2-epoxyhexane, epoxystyrene and epoxycyclohexane under mild conditions to produce respective epoxides and diols in high yield and ee (Table 2). 

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