Aldol catalysts

Morken and co-worker (58) used a similar approach for the discovery of a selective reductive aldol catalyst. Through screening 192 different sets of reaction conditions Morken settled on a rhodium system shown in Scheme 28. This system is an excellent example of the power of this type of approach. Three parameters were screened simultaneously. It was shown that the selectivity and yield of the reaction are dependent on the hydride source, transition metal and ligand used on that transition metal. In this case, GC was used to evaluate the results. 

Analogs of Nomicotine - an Aldol Catalyst Exemplifying Natural Toxicity 179... 

Nomicotine, an organocatalyst studied by Dickerson and co-workers (Entry 5 [52, 58d], Appendix 7.B), reinforces the important principle that even catalysts from Nature can present problems when it comes to toxicity. The family of nicotinic receptor agonists (Figure 7.9) contains several chiral pyrrolidines and piperidines with the potential to act as asymmetric aldol catalysts. Nomicotine, which can be isolated from plants such as tobacco, or readily synthesized by demethylation of the maj or tobacco alkaloid nicotine, was investigated in some depth as an aldol catalyst by Dickerson and Janda in 2002 [52]. 

Figure 7.15 Adamantyl-linked proline is an effective aldol catalyst in the presence of 3-cyclodextrin.

Even considering only the example of the proline family of aldol catalysts, it is dear that there will soon be hundreds of cases of organocatalysts described in the literature. Direct, organocatalytic aldol reactions do not yet have the generality of traditional stoichiometric methods, which can offer predictable results for a wide variety of substrates. However, companies already offer to screen substrates against panels of up to 200 enzymes to find the optimum biocatalyst for a reaction, and the same approach could be applied to identify rapidly the best organocatalyst for a process. 

Antibody Catalysis. Recent advances in biocatalysis have led to the generation of catalytic antibodies exhibiting aldolase activity by Lemer and Barbas. The antibody-catalyzed aldol addition reactions display remarkable enantioselectivity and substrate scope [18]. The requisite antibodies were produced through the process of reactive immunization wherein antibodies were raised against a [Tdiketone hapten. During the selection process, the presence of a suitably oriented lysine leads to the condensation of the -amine with the hapten. The formation of enaminone at the active site results in a molecular imprint that leads to the production of antibodies that function as aldol catalysts via a lysine-dependent class I aldolase mechanism (Eq. 8B2.12). 

Diketone 4 was used for immunization, and two out of twenty monoclonal antibodies produced showed the characteristic enaminone absorb-tion at 315 nm after incubation with the diketone. Only these two antibodies, 38C2 and 33F12, were aldol catalysts (Wagner et al 1995). For example, 38C2 catalyzes the aldol reaction between acetone and aldehyde 5 to give aldol 6 with cat = 6.7 X 10 3 min-1 and = 17 (Scheme 4). 

One of the most powerful catalysts of the Mukaiyama aldol reaction is a chiral Ti(IV)-Schiff base complex 91 prepared from Ti(0 Pr)4 and enantiomerically pure salicylaldimine reported by Carreira [103-105]. This catalyst furnished aldol adducts in good yields and with excellent enantioselectivity. The Ti(IV)-Schiff base catalyst system is unique among the aldol catalysts yet reported in terms of operational simplicity, catalyst efficiency, chirality transfer, and substrate generality. Because the Ti(IV)-Schiff base complexes are remarkably efficient catalysts for the addition of ketene acetals to a wide variety of aldehydes, the polymeric version of catalyst 92 was prepared [106]. The activity and enantioselectivity of the polymer-supported chiral Ti(IV)-Schiff base complex were, however, much lower than were obtained from the low-molecular-weight catalyst (Eq. 28). 

Vince S. C. Yeh received his B.S. degree (1994) from the University of British Columbia where he participated in undergraduate research under the late Professor L. Weiler. He completed Ph.D. (2001) from the University of Alberta under the guidance of Professor D. L. J. Clive, where he studied the asymmetric syntheses of alkaloids. After postdoctoral research (2003) with Professor B. M. Trost at Stanford University on asymmetric aldol catalysts, he joined Abbott Laboratories as a senior research chemist working in the area of metabolic diseases. His research interests include drug discovery, asymmetric synthesis, and natural products. 

The smooth condensation of 2,2 -diacetylbiphenyl to dibenzotropone in the presence of bis[4-methoxyphenyl] tellurium oxide is remarkable in view of previous unsuccessful attempts to effect this cyclization with conventional aldol catalysts. Diaryl telluroxides are poor catalysts for aldol condensations involving acidic methylene groups, because formation of tellurium ylides removes the catalyst. ... 

A related Mukaiyama aldol catalyst system reported by Keck prescribes the use of a complex that is prepared in toluene from (R)- or (S)-BINOL and Ti(0 Pr)4 in the presence of 4 A molecular sieves. In work preceding the aldol addition reaction, Keck had studied this remarkable catalyst system and subsequently developed it into a practical method for enantioselective aldehyde allylation [95a, 95b, 95c, 96]. Because the performance of the Ti(IV) complex as an aldol catalyst was quite distinct from its performance as a catalyst for aldehyde allylation, a careful examination of the reaction conditions was conducted. This meticulous study describing the use of (BINOL)Ti(OiPr)2 as a catalyst for aldol additions is noteworthy since an extensive investigation of reaction parameters, such as temperature, solvent, and catalyst loading and their effect on the enantiomeric excess of the product was documented. For example, when the reaction of benzal-dehyde and tert-butyl thioacetate-derived enol silane was conducted in dichlo-romethane (10 mol % catalyst, -10 °C) the product was isolated in 45% yield and 62% ee by contrast, the use of toluene as solvent under otherwise identical conditions furnished product of higher optical purity (89% ee), albeit in 54% yield. For the reaction in toluene, increasing the amount of catalyst from 10 to 20 mol %... 

Since these initial publications, the considerable efforts of Shibasaki and coworkers have lead to lanthanide element-binaphtholato complexes as being the most developed and potent of asymmetric phospho-aldol catalysts. From their early work on catalysis in the nitro-aldol reaction [28], Shibasaki and co-workers have published widely and in considerable detail on the use of hetero-bimetallic catalysis, developing the field to such a degree that enzyme-like comparisons have been made. Much of the success of the Shibasaki team in hetero-bimetallic catalysis has been reviewed recently [29], the key to which has been the delineation of the solid state structures of the catalytic precursors via single crystal X-ray diffraction studies [30] (Fig. 1) and the development of improved synthetic routes to this class of heterobimetallic system (Scheme 12) which emphasise the important role of added water [31]. 

Hydroformylation of ethylene using a water-soluble Rh-TPPTS catalyst has been investigated [27] using a toluene-water solvent system at 353 K. The effect ofTPPTS concentration on rate shows a maximum at a P/ Rh ratio of 8 1. The rate of reaction first increases with catalyst concentration, and above a certain value it remains constant. The effect of aqueous-phase hold-up shows a maximum in the rate at = 0.4. The apparent reaction orders for the partial pressures of hydrogen and ethylene were found to be one and zero respectively. A strong inhibition in the rate with an increase in Pqq was observed. An interesting example of tandem synthesis of methacrolein in an aqueous biphasic system has been reported by Deshpande et al. [28], in which hydroformylation of ethylene and aldol condensahon reactions occur in two immiscible liquid phases with a high yield of the product Use of a two-phase system prevents contact of the hydroformylation and aldol catalysts, the interaction of which leads to deactivation. 

Very recently N-terminal prolyl peptides have been suggested as another attractive class of aldol catalyst. Tang et al. [132] mention in a footnote that the dipeptide Pro-Thr-OMe catalyzes the reaction of acetone with p-nitrobenzaldehyde to give the corresponding aldol in 69% ee. Reymond et al. have studied a peptide library and also found that several N-terminal prolyl peptides catalyze the same asymmetric aldolization [124]. Independently, Martin and List showed that N-terminal prolyl peptides catalyze the direct asymmetric aldol reaction of acetone with p-nitrobenzaldehyde and the asymmetric Michael reaction between acetone and j5-nitrostyrene (Scheme 4.37) [135]. Mechanisms have so not yet been proposed for these reactions. 

E. Development of chiral metal complexes as Le vis acid aldol catalysts. 

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