Proline catalysts addition

Reaction progress kinetic analysis offers a reliable alternative method to assess the stability of the active catalyst concentration, again based on our concept of excess [e]. In contrast to our different excess experiments described above, now we carry out a set of experiments at the same value of excess [ej. We consider again the proline-mediated aldol reaction shown in Scheme 50.1. Under reaction conditions, the proline catalyst can undergo side reactions with aldehydes to form inactive cyclic species called oxazolidinones, effectively decreasing the active catalyst concentration. It has recently been shown that addition of small amounts of water to the reaction mixture can eliminate this catalyst deactivation. Reaction progress kinetic analysis of experiments carried out at the same excess [e] can be used to confirm the deactivation of proline in the absence of added water as well to demonstrate that the proline concentration remains constant when water is present. 

A different type of catalysis is observed using proline as a catalyst.166 Proline promotes addition of acetone to aromatic aldehydes with 65-77% enantioselectivity. It has been suggested that the carboxylic acid functions as an intramolecular proton donor and promotes reaction through an enamine intermediate. 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

With regard to the mechanism of this new type of reaction, the Jorgensen group postulated enamine formation, by addition of the catalyst to the nitrone, followed by hydroxylamine elimination [132], Subsequent aldol-type reaction of this enamine with the carbonyl component and release of the proline catalyst by exchange... 

In an extension to the above methodology, a sequential 1,2-addition, dehydration, and in situ ring closure via a 67t-electron electrocyclic cyclization has been described in the context of the pharmacologically relevant natural products warfarin A, the arisugacins, merulidial, and isovelleral (Scheme 20) <2005CAR1287>. Carbohydrate-derived a,3-unsaturated enals were coupled with 4-hydroxycoumarin 188 and 4-hydroxy-6-methylpyran-2//-one 191 in the presence of proline catalysts to provide pyrone-annulated products of types 190 and 192. Stereoselective electrocyclic ring closure was observed only when hydroxyl functionality (at any of R -k ) on the enal was acyl protected. 

Slow addition of the vinyldiazomethanes 1059 to a stirred solution of rhodium(ll) octanoate and 2-substituted iV-BOC-pyrroles 1058 in refluxing hexane resulted in the formation of the tropanes 1060 in 53-70% de (30-82% yield) (Equation 250) <1997JOC1095>. Unlike the results seen with the prolinate catalysts (Equations 246 and 247), no [3.3.0]- or [4.2.0]-bicyclic products are formed in these reactions in most cases. Furthermore, the tropane regioselectivity is greater than 10 1 favoring the products derived from initial cyclopropanation at the unsubstituted double bond of the pyrrole. 

Hydroformylation of olefins has been established as an important industrial tool for the production of aldehydes. In recent years, novel asymmetric tandem reactions have included a rhodium-catalysed enantioselective hydroformylation. In this context, in 2007 Abillard and Breit ° and Chercheja and Eilbracht independently reported a novel domino hydroformylation-aldol reaction catalysed by an achiral rhodium catalyst and L-proline catalyst (Scheme 7.49). Possibly owing to the fact that proline is hard but the rhodium catalyst is soft, the proline can be compatible with the rhodium catalyst to allow this domino reaction to be achieved. By fine adjustment of the hydroformylation rate to that of the L-proline-catalysed aldol addition, the undesired homodimerisation of the aldehyde could be avoided. As a result, by in situ hydroformylation reaction, the donor aldehyde of a... 

Stable zirconium methyl- and/or phenylphosphonates (696) functionalised with (4J )-4-[4 -(phosphonatobenz-yl)o3y]-l-proline groups have been prepared by Piermatti and co-workers. The supported L-proline catalysts (696) have been tested in the direct asymmetric aldol addition affording products in high yields, diastereselectivities [antUsyn up to 92 8) and enantiomeric excesses (up to 99% ee). Moreover, it has been shown that these L-proline immobilised catalytic systems can be used at least six times without loss of activity and with reproducible anti/syn and ee values. ... 

What is the role of water under these conditions It has been suggested that water suppresses the formation of proHne-oxazoUdinone, which has been considered to be a parasitic species [11]. Then, the role of water is to prevent deactivation rather than to promote activity. Studies, carried out on the proUne-catalyzed reaction between acetone and 2-chlorobenzaldehyde allow one to hypothesize a conflicting role of water. Water increases the total catalyst concentration due to suppression of unproductive species and decreases the relative concentration of productive intermediates by shifting the iminium ion back to proline [12]. Addition of water suppresses formation of both on- and ofF-cyde iminium ions 1 and 2 by Le Chatelier s principle (Scheme 24.2a). The net effect of added water on the globally observed rate will depend on the relative concentrations of iminium ions 1 and 2, which may be different for different aldehydes and can be a function of substrate concentrations and rate and equilibrium constants. Seebach and Eschen-moser have raised doubts about the fact that oxazoUdinones are unproductive and parasitic species in proline-catalyzed aldol reactions [13]. The small excess of water will potentially facilitate proton-transfer in the transition state (Scheme 24.2b), which both lowers the LUMO of the incoming electrophile as well as directs the enantioselectivity of the newly formed stereocenters. 

The most famous secondary amine employed in organocatalysis is proline. In addition to the examples reported in the introduction regarding the use of proline under aqueous conditions, it is worth further describing other apphcations of proline under the same conditions. No enantioselectivily was observed in prohne-catalyzed aldol reactions in phosphate buffer [38] and aqueous micelles [39]. When proline was used with camphorsulfonic acid as co-catalyst good yields and stere-oselechvities were obtained using a 4 1 (v/v) ketone water ratio [40]. 

At almost the same time. Ley and coworkers reported the use of tetrazole proline catalyst for the addition of nitroalkanes to enones [93]. As in Hanessian s example, this protocol requires the use of an amine additive. In this case, the enantioselectivities obtained were excellent, albeit with moderate yields. 

In a sequence that is the equivalent of an oxocarbenium-induced C-C bondforming reactirai, McQuade and coworkers have used organic catalysts to carry out the coupling of 2-hydroxy tetrahydrofuran 48 with methyl ketones 49 to give 2-alkyl furans (Scheme 15) [13]. Mechanistically the reaction is proposed to proceed through the addition of a thiourea-stabiUzed enolate from the reaction of 49 with 51 to an iminium intermediate that comes from the condensation of 48 with proline catalyst 50. Hydrolysis and Michael cyclization or displacement of the ammonium ion subsequent to the Mannich reaction gives the observed product 52. 

In the early 1970s, i-proline (222) was shown to function as a chiral catalyst for enantioselective aldol addition reactions (Chapter 4) [156]. With the aim of expanding the scope of proline-catalyzed asymmetric aldol additions [157], List reported that proline also catalyzes enantioselective Mannich reactions (Equation 19) [158]. Whereas most catalytic enantioselective Mannich reactions with aldehydes typically afford the corresponding syn products, Barbas, Tanaka, and Houk demonstrated that the complementary anti products such as 232 could be obtained highly selectively in the presence of the methyl-substituted proline catalyst 229 (99% ee, 98 2 dr. Scheme 11.33) [159]. It was proposed that these transformations proceeded through the energetically favored enamine 230 and transition state structure 231. 

As an alternative, tin enolates are very useful in these additions. Usually they are prepared in situ from the amide using tin(II) trifluoromethanesulfonate and a base. They are subsequently reacted with an enone, catalyzed by a Lewis acid47-48 (see Table 3). With triinethylsilyl trifluoromethanesulfonate as a catalyst, in the presence of proline derived diamines anti-adducts are formed exclusively49 (see Section 1.5.2.4.3.1.). 

Kragl and Dreisbach (1996) have carried out the enantioselective addition of diethyl zinc to benzaldehyde in a continuous asymmetric membrane reactor using a homogeneous soluble catalyst, described in their paper. Here a,a-diphenyl-L-proline was used as a chiral ligand, coupled to a copolymer made from 2-hydroxy ethyl methacrylate and octadecyl methacrylate, which had a sufficiently high molecular weight to allow separation by ultra-filtration (U/F). The solvent-stable polyaramide U/F Hoechst Nadir UF PA20 retained more than 99.8% of the catalyst. The ee was 80 %, compared to 98 % for a noncoupled catalyst. 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

---