Tripeptide catalysts

Intramolecular enantiosituselectivity is exemplified by the biosynthetic formation of the mustard oil glucoside sinigrin (60) in horseradish, " the deprotonation of N-Boc-pyrrolidine (62) with sec-butyllithium (s-BuLi)/(-)-sparteine, followed by methylation, "" and, the oxidation of enol 64. Intermolecular enantiosituselective transformations are exemplified by the hydrolysis of racemic N-dodecanoylphenylalanine p-nitrophenyl esters (( )-67) in the presence of tripeptide catalyst (Z)-L-Phe-L-His-L-Leu (68) in each of the latter two cases, only one (externally) enantiotopic carbonyl reacts preferentially. It should be pointed out parenthetically, that as a result of the enantiosituselectivity in these transformations, one has, in effect, kinetic resolution of ( )-67. The electron-impact induced elimination in acetate 71, and the oxidation of 73 exemplify intramolecular diastereosituselective transformations. The epoxidation of the mixture 76/77 is an example of an intermolecular diastereosituselective process at the same time that each substrate is subject to enantiositunonselectivity of the carbonyl sub-sites. 

Uoeka and coworkers focused their efforts on the development of a catalytic system of a dipeptide or tripeptide containing L-histidine [47]. An enhanced enan-tioselective hydrolysis was obtained with a tripeptide catalyst in a mixed surfactant system. The tripeptide Z-L-Phe-L-His-L-Eeu-OH was the most efficient catalyst for the hydrolytic cleavage of p-nitrophenyl N-acylphenylalanylates. 

To a much smaller extent non-enzymic processes have also been used to catalyse the stereoselective acylation of alcohols. For example, a simple tripeptide has been used, in conjunction with acetic anhydride, to convert rram-2-acctylaminocyclohexanol into the (K),(R)-Qster and recovered (S),(S)-alcohol[17]. In another, related, example a chiral amine, in the presence of molecular sieve and the appropriate acylating agent, has been used as a catalyst in the conversion of cyclohexane-1(S), 2(/ )-diol into 2(S)-benzoyloxy-cyclohexan-1 f / j-ol1 IS]. Such alternative methods have not been extensively explored, though reports by Fu, Miller, Vedejs and co-workers on enantioselective esterifications, for example of 1-phenylethanol and other substrates using /. vo-propyl anhydride and a chiral phosphine catalyst will undoubtedly attract more attention to this area1191. 

The first catalyst of this type to be reported by Miller was tripeptide 48 in 1998 which adopts a ]3-tum type structure possessing one intramolecular hydrogen bond [159]. In addition, this organocatalyst judiciously incorporates a C-terminal R)-a-methylbenzylamide which prompts ji-ji stacking interactions (Scheme 17) [159]. 

Asymmetric phase-transfer catalysis with (S,S)-lg can be successfully extended to the stereoselective N-terminal alkylation of Gly-Ala-Phe derivative 61 (i.e., the asymmetric synthesis of tripeptides), where (S,S)-lg turned out to be a matched catalyst in the benzylation of DL-61, leading to the almost exclusive formation of DDL-62. This tendency for stereochemical communication was consistent in the phase-transfer alkylation of DDL-63, and the corresponding protected tetrapeptide DDDL-64 was obtained in 90% yield with excellent stereochemical control (94% de) (Scheme 5.30) [31]. 

Hebach and Kazmaier reported the synthesis of cyclic peptidomimetics containing an alkylated amino acid via Ugi-4CR of N-terminal-protected aloc-amino acids, allyl isocyanoacetate, and chiral amines in trifluoroethanol. Allylic esters of tripeptides 193 were obtained in high yields and good stereoselectivity. Metathesis with 5% of Grubbs first-generation catalyst gave 16-membered cyclic peptides 194 in 30-50% yield (Scheme 2.69) [101]. 

In addition to phosphines and pyridines, N-alkylated imidazoles are also known to act as a nucleophilic catalysts in acylation reactions [1], In the approach by Miller et al. short oligopeptides incorporating N-alkylhistidine derivatives were used as enantioselective acylation catalysts [27]. The design of, e.g., the tripeptide... 

An asymmetric version of a Michael addition with nitrogen nucleophiles can be also realized with simple short-chain peptides as catalysts. This has been demonstrated by Miller et al. for the addition of an azide to a,/(-unsaturated carbonyl compounds [16]. In the presence of the tripeptide 9 as a catalyst (2.5 mol-%) the products 10 have been formed in excellent yields and with up to 85% ee (Scheme 7). In addition, this reaction represents an attractive access to /(-amino acids. 

Racemic haptens have the advantage of synthetic expedience, but they do not always yield (R)- and (S)-specific catalysts in a single experiment. The eighteen catalytic antibodies obtained with the tripeptide phosphonate 6,14 for example, only catalyzed the hydrolysis of substrates (7) containing D-phenylalanine at the cleavage site. Depsipeptides containing leucine or tryptophan in place of phenylalanine were not hydrolyzed. The selectivity for d- over... 

A more general and highly diastereoselective Mannich-type reaction was developed by Ohshima and Shibasaki. The tartrate-derived diammonium salt 43c possessing 4-fluorophenyl substituents was identified as an optimal catalyst for the reaction of 28 with various N-Boc imines under solid (Cs2CC>3)-liquid (fluoroben-zene) phase-transfer conditions, as exemplified in Scheme 4.24 [64]. The usefulness of the Mannich adduct 67b was further demonstrated by the straightforward synthesis of the optically pure tripeptide 68. 

Miller has developed various short peptides containing 3-(l-imidazolyl)-(S)-alanine as the catalytic core these biomimetic enantioselective acyl transfer catalysts allow the formation of an acyl imidazolium intermediate in a chiral environment formed by folding of the peptide [109-123]. The first catalyst of this type to be reported was tripeptide 27 in 1998 [109]. This peptide incorporates a C-terminal (R)-methylbenzylamide to encourage order-inducing stacking interactions in the acylimidazolium intermediate (Scheme 8.6). 

This tripeptide provided moderate levels of selectivity (s < 12.6) for the KR of certain amide-containing sec-alcohols (see Section 8.2.1.4), but displayed essentially no selectivity for KR of aryl alkyl sec-alcohols. However, Miller subsequently devised an elegant fluorescent chemosensor-based screening protocol to assay for acylation [111, 115, 117, 119], and this facilitated the identification of octapeptide 28 as a much more efficient catalyst for KR of sec-alcohols via acylation [115]. The substrate scope includes not only aryl alkyl sec-alcohols but also alkyl alkyl sec-alcohols for which lipases and other organocatalysts invariably perform poorly (Scheme 8.7). 

The situation vis-a-vis H-bonding interactions is not dissimilar. The importance of H-bonding interactions was first demonstrated in Miller s studies on acylative KR using imidazole-containing peptides beginning in 1998, and appears to be a key feature of these catalysts [109-123]. As described earlier, tripeptide 27 provides essentially no selectivity in attempted acylative KRs of aryl alkyl sac-alcohols, but catalyzes KR of trans-2-(N-acetylamino)-cyclohexan-l-ol with good selectivity (s = 12.6) due at least in part to the H-bond donor properties of the acetamide NH group (Scheme 8.13) [109]. 

Trans stereochemistry, 41, 106 Transesterification, 85, 90 Transfer ribonucleic acid (tRNA), 37 Transition metal catalysts, 110 Triacontane, 18 Triblock copolymers, 102 Trimec, 262 Tripeptides, 28-30 acidic, 30 Tryptophan, 29 Tyrosine, 29 Tyvek, 170,170... 

Strecker-type addition of cyanide to imines has been reported to be catalyzed by chiral Ti Schiff base-tripeptide complexes (Sch. 65) [161]. The reaction is efficient (> 93 % conversion) and proceeds with excellent enantioselectivity (85-97 % ee) in the presence of 1.5 equiv. 2-propanol. Hoveyda and Snapper pointed out that catalyst turnover is significantly facilitated by the presence of 2-propanol. Optically pure products are usually isolated in > 80 % yields. 

Poly(ethylene glycol) grafted on crosslinked polystyrene (PEG-PS) resin has often been used as a polymer support for chiral catalysts of reactions performed in aqueous media. Peptides immobilized to PEG-PS resin have been developed and used as a catalyst for direct asymmetric aldol reactions in aqueous media (Scheme 3.19) [42]. When tripeptide-supported PEG-PS 67 was used as chiral catalyst in the reaction between 70 and acetone, the corresponding aldol product 69 was obtained with 73% ee. Kudo further developed the one-pot sequential reaction of acidic deacetalization and enanhoselective aldol reaction by using an Amberhte and PEG-ST-supported peptide catalyst 67 [43]. The enantioenriched aldol product 72 was obtained in 74% isolated yield from acetal 70 in a one-pot reaction (Scheme 3.20). 

Wennemers found that tripeptide H-Pro-Pro-Asp-NH2 was a highly active and selective catalyst for asymmetric aldol reactions [44]. This peptide was immobihzed to a polymer support and used as a catalyst for the aldol reaction of p-nitrobenzal-dehyde 73 and acetone (Scheme 3.21). By using a TentaGel-supported peptide 73 the aldol adduct 69 was obtained in 89% yield with 75% ee, while a polyethylene glycol-polyacrylamide (PEGA)-supported peptide gave the same adduct in 93% yield and 79% ee [45]. 

The enhancement of reaction rate as well as the stereoselectivity of hydrolytic reactions were studied by several authors [47]. Typical substrates were hydro-phobized activated esters of amino acids and typical catalysts were surface active peptides with histidine as active component. The kinetic resolution of racemic esters was determined. Brown [48] and Moss [49] gave explanations for the stereoselectivity. Ueoka et al. [50] reported one example where non-function-al amphiphiles as cosuxfactants can enormously improve the stereoselectivity the saponification of D,L-p-nitrophenyl J -dodecanoylphenylalaninate with the tripeptide Z-PheHisLeu-OH as catalyst in assemblies of ditetradecyldimethylam-monium bromide yielded practically pure L-M-dodecanoylphenylalanine upon the addition of between 7 to 20 mol % of the anionic surfactant sodium dodecyl sulfate (SDS). 

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