Phenylalanine derivatives, catalyst

Jorgensen et al. developed the phenylalanine-derived catalyst 51 (Scheme 4.20), readily prepared in three high-yielding steps from L-phenylalanine, methylamine, and glyoxylic acid [34, 35]. 

The first organocatalytic intermolecular asymmetric aldol reaction was reported by List and coworkers in 2000 [23]. The aldol reaction between acetone and a variety of aldehydes was accomplished in excellent yields and high levels of e-nantioselectivity. For example, the aldol product of the coupling with o-butyral-dehyde was formed in 97 % yield and 96 % ee ((1), Scheme 4.10). The remarkable levels of selectivity sparked massive interest in the field of proUne-catalysed aldol, Michael and Mannich reactions. Later that year MacMillan reported a phenylalanine-derived catalyst (35) for the Diels-Alder reaction of a-P-unsaturated aldehydes with up to 94 % ee ((2), Scheme 4.10) [24]. Many further applications of... 

Inspired by the proline-catalyzed Robinson annulation pioneered by Wiechert, Hajos, Parrish and coworkers [39], they were able to construct cyclohexanones of type 2-107 with up to four stereogenic centers with excellent enantio- and di-astereoselectivity from unsaturated ketones 2-104 and acyclic (l-ketoesters 2-105 in the presence of 10 mol% phenylalanine-derived imidazohdine catalyst 2-106. The final products can easily be converted into useful cyclohexanediols, as well as y- and e-lactones. 

Aldehydes bearing a-hetero substituents also typically afford anti products, and the general solution to syn selective a-heteroatom substituted aldehyde-aldehyde aldol processes via enamine catalysis also still remains to be discovered. Nevertheless, the anti process is remarkably useful because a variety of highly substituted aldehydes can be accessed in a single operation using only very inexpensive catalysts, such as proline 6 or the phenylalanine-derived imidazohdinone 46 (Scheme 21) [114, 116, 117, 119-121, 188]. 

Based on the concept mentioned above, Brown realized the asymmetric deactivation of a racemic catalyst in asymmetric hydrogenation (Scheme 9.18) [35]. One enantiomer of (+)-CHIRAPHOS 28 was selectively converted into an inactive complex 30 with a chiral iridium complex 29, whereas the remaining enantiomer of CHIRAPHOS forms a chiral rhodium complex 31 that acts as the chiral catalyst for the enantioselective hydrogenation of dehydroamino acid derivative 32 to give an enantio-enriched phenylalanine derivative... 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

The Jacobsen group have also focused on optimization of the organocatalyst, and the design of new, simpler catalysts [37], by systematic variation of each modular component of the catalyst, for example the salicylaldimine, diamine, amino acid, and amide. A new catalyst was found, a simple amino acid derivative 42 with less than half the molecular weight and fewer stereogenic centers than the thiourea catalyst 41. In the presence of this organocatalyst 42, benzaldimine was converted into the corresponding //-phenylalanine derivative (R)-40a with 100% conversion and 94% ee (Scheme 5.24) [37]. 

The MacMillan group has also shown that cycloaddition reactions (see also Chapter 8) can be performed highly diastereo- and enantioselectively. The [3+2]-cycloaddition of nitrones and a,/i-un saturated carbonyl compounds in the presence of 20 mol% of a phenylalanine-derived imidazolidinone acid salt led to products with 99% ee [32]. An example of an enantioselective rearrangement reaction (see also Section 13.6) with 99% ee has been reported by the Fu group [33], who used 2 mol% of a planar chiral DMAP derivative as catalyst. 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

The phenylalanine-derived chiral amine catalyst 10 was used to promote the asymmetric [4-1-3] cycloaddition between 2,5-dialkylfurans and trialkylsilyloxypentadienals to generate seven-membered carbocycles with OTrfo-selec-tivity and 81-90% ee, as represented in Equation (46) <2003JA2058>. However, the absolute configurations of the cycloadducts have not been determined. 

Amphiphilic diblock copolymers based on 2-oxazoline derivatives with chiral diphosphine 187 were prepared (Scheme 3.61) and used in the asymmetric hydrogenation of methyl (Z)-(z-acelarnido cinnamate 188 in water to give the (R)-phenylalanine derivative 189 in 85% ee [124]. The polymeric catalyst could be recycled. This result illustrated the advantages of using amphiphihc copolymers for the efficient transformation of a hydrophobic substrate in water. 

Other chiral organic catalysts of major success are the protonated phenylalanine-derived imidazohnones 28 developed by MacMillan [48], that have found widespread use in a number of relevant processes [5, 6]. Immobihzed versions of these catalysts have been developed both on soluble (PEG-supported catalyst 29 [49]), and insoluble supports (catalysts 30 and 31 [50]), and employed in enantioselechve Diels-Alder cycloadditions of dienes with unsaturated aldehydes (Scheme 8.16). 

The asymmetric catalyst is based on the chiral bisphosphine, / ,/ -DlPAMP (18), that has chirality at the phosphorus atoms and can form a hve-membered chelate with rhodium. The asymmetric reduction of the Z-enamide proceeds in 96% ee (Scheme 9.19)." The pure isomer of the protected amino acid intermediate 19 can be obtained upon crystallization from the reaction mixture as it is a conglomerate." Although the catalyst system is amenable to the preparation of a wide variety of amino acids, especially substituted phenylalanine derivatives," " a major shortcoming of the approach is the need to have just the Z-enamide isomer as the substrate. 

The catalysts 11 and 12 (Fig. 4) were used for the synthesis of phenylalanine derivatives (Scheme 7) [28]. Besides the SAPC system, both the homogeneous hydrogenation and the aqueous-biphasic system were investigated. The supported complex 11, like the homogeneous analogue, showed poor performance as far asenantio selectivities are concerned. In contrast, the aqueous-biphasic catalyst performed at least moderately enantioselective. In this context enhanced selectivity was achieved with immobilized catalyst 12. The increased ee values (from 16 to 55%) were obtained at the expense of an extended reaction time, which increased from 2 to 40 h. 

Two total syntheses of pyrrolidine alkaloids have been reported. (—)-Codonopsinine (85), an imino-pentitol which exhibits antibiotic and hypotensive activity, has been synthesized in seven steps in 16% overall yield from dihydropyrrole 84. The enantioselective synthesis of the potent antifungal agent (-l-)-preussin (87) has also been achieved from L-phenylalanine derivative 86. The pyrrolidine skeleton was established by hydrogenolysis of an intermediate oxazoline and subsequent diastereoselective reductive cyclization of the resultant aminoketone using Pearlman s catalyst. ... 

However, even though this reaction proceeds in a very efficient way when an aromatic aldehyde is employed as the Michael donor, the use of aliphatic aldehydes is much more problematic due to the intrinsic instability of enoliz-able aldehydes in the basic media required in the reactions catalyzed by A-heterocyclic carbenes. In fact, pre-catalyst 119a performed poorly in this case, but this limitation was overcome with the use of bicyclic triazolium salt 120a derived from phenylalanine as catalyst precursor. This new A-heterocyclic... 

Subsequently, the Rovis group reported an intermolecular Stetter reaction of morpholine-derived glyoxamides with p-substituted alkylidene malonates or alkylidene ketoamides in the presence of a phenylalanine-derived carbene catalyst. During the reaction condition optimization, it was found to be necessary to use one equivalent of Hiinig s base and add magnesium sulfate to ensure the high enantioselectivity (Scheme 7.25). 

---