Tetrazoles proline

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. 

Tetrazole proline derivative 24 has shown to be superior to proline as catalyst in the reaction of substituted aldehydes with DEAD (18b) to yield the expected a-amino aldehyde with good enantioselectivity (65-88% ee). In the case of using proline, the enantioselectivity was only 44% and the time increased from 3 h to 5 days. The higher reactivity and selectivity of catalyst 23 compared to proline was attributed to the lower pK (8 in DMSO, 12 for proline) and its higher steric hindrance [21]. 

Even different chiral dihydro-1,2-oxazine derivatives were obtained when the enantioselective a-aminoxylation reaction was catalyzed by tetrazole proline derivative 24, in which the in sim formed aldehyde 66 reacted subsequently with vinylphosphonium salt derivatives or Grignard reagents [89]. 

Type A enamine catalysts include simple amino acids, such as proline 6, and most of their derivatives (such as the tetrazole 44 and various sulfonamides, e.g. 45). They are typically used for aldol, Mannich, a-amination and a-oxygenation reactions - these are all reactions where the electrophile can readily be activated by hydrogen bonding (Scheme 12) [8, 9, 12, 46],... 

L-Proline (S)-3-(2-Pyridyl)pyrrolidine (5)-3-(2-Pyridyl)piperidine (S)-3-(2-Pyridyl)tetrazole... 

Figure 3.38 a The general enamine catalytic cycle in the presence of L-proline b an example of an asymmetric Mannich-type addition of cyclohexanone to iminoethyl glyoxalate, catalyzed by a proline tetrazole derivative. 

Enantioselective aldolization using 5-pyrrolidin-2-yltetrazole (26) - in which the carboxylic acid of proline has been replaced by its well-known pharmacophore - has been modelled by DFT.112 The calculations indicate that the large charge buildup on the carbonyl oxygen during C-C bond formation is stabilized by hydrogen bonding by the tetrazole NH. 

The use of different acid functionalities on pyrrolidine-derived catalysts has improved the reaction rate of some aldol reactions. For example, pyrrolidine-based tetrazole derivative 9 (Fig. 2.2) catalyzed many aldol reactions with rates faster than proline, with similar stereocontrol [16, 18b, 24, 55]. The faster reaction rates with tetrazole derivative 9 in DM SO as compared with proline were attributed to the lower pKa of the tetrazole moiety as compared to the carboxylic acid group in DMSO (tetrazole pKa(DMSO) 8.2 acetic acid pKa(DMSO) 12.3) [55, 56]. In addition, tetrazole derivative 9 is more soluble than proline in many organic solvents. A higher actual concentration of the catalyst in the solution phase of a reaction mix-... 

Fig. 2.2 Proline and its tetrazole derivative used for aldol reactions [55, 56].

Proline derivatives, such as (2S,4R)-4-hydroxyproline (2), (2S,4R)-4-tert-butoxy-proline, (2S,3S)-3-hydroxyproline [71b] and tetrazole-containing pyrrolidine 9 [75] also catalyzed the Mannich-type reactions using aldehydes as nucleophiles via enamine intermediates, and afforded the syn-isomer as the major diaster-eomer with high enantioselectivity at room temperature. On the other hand,... 

The same authors have shown that the direct a-amination reaction could also be used to construct the quaternary stereocenter in the enantioselective total synthesis of the cell-adhesion inhibitor BIRT-377 [7b]. The i-proline-derived tetrazole 3c catalyzed the direct a-amination of 3-(4-bromophenyl)-2-methylpropanal 8 with dibenzyl azodicarboxylate 2b to give the amino aldehyde 9 in 95% yield and with... 

A number of organocatalysts such as derivatives of proline and morpholine were screened by Barbas group and the tetrazole catalyst 26 gave the best result, with 95 % yield and 80 % ee. The enantiomerically enriched mixture could be recrystallized to yield 71 % of aminoaldehyde 27 in >99 % ee. 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

Cordova and co-workers [163] reported simultaneously a similar approach for the synthesis of protected 4-amino-4-deoxy-threo-pentulose and 4-amino-4-deoxyfructose (O Scheme 32). The catalyst can be L-proline, other o -aminoacids, or alanine-tetrazole [126]. 

Noting the similarity of (NH) tetrazole pKs to those of carboxylic acids, tetrazoles have often been used as bioequivalent replacements for CO2H, and as general variants, in pharmacologically active compounds (Chapter 33). The acid replacement extends to the tetrazole analogue of proline (p. 567), which is more solnble than proline itself, but retains its catalytic properties for condensation reactions. 

A representative set of such structures (7.80-7.86) is shown, all of which result in the formation of aldol adducts with high ee. Replacement of the carboxylic acid moiety with a bioisosteric tetrazole results in a catalyst (7.80) that is both more reactive than L-proline (7.66) and more readily soluble in organic solvents such as THF.38a.b jji a similar vein, acyl sulfonamides such as (7.81) give good enantios-electivities in the aldol reaction with aromatic aldehydes in organic solvents such as dichloromethane and acetone. 3 The addition of stoichiometric amounts of water increases the activity of tetrazole (7.80) further and this allows the use of aldehydes such as chloral monohydrate (7.87) and formaldehyde, which have an affinity for water and are generally poor substrates for the catalytic asymmetric aldol reaction. 38 = Catalysts (7.82)38 (7.33) 3Sd ijpophilic substiments,... 

As the intermediate enamine reacts faster with imines than aldehydes, a one-pot three component coupling of the donor ketone, aldehyde and amine is possible. List and coworkers have achieved high ees in this reaction utilising L-proline (7.66) and some aliphatic aldehydes and aromatic aldehydes such as (7.136) in combination with p-anisidene (7.137). This catalyst system is also effective for the coupling of a-hydroxyketones. Use of the tetrazole-substituted proline (7.80) allows the reaction to be performed in dichloromethane rather than DMSO and high ees in the Mannich reaction between aliphatic ketones and imines derived from ethyl glyoxalate have been obtained imder these reaction conditions. 

Scheme 2.5 Enantioselective Michael reactions of ketones with nitroalkenes catalyzed by proline and proline-tetrazole analogues.

Two different models were proposed by Ley for the 2b-catalyzed reaction which should also be of application for the cases of proline 1 and proline-tetrazole catalysts 2a, both of them in good agreement with the observed absolute configuration of the final Michael adducts (Figure 2.2). One proposal involved the possibility of the tetrazole moiety acting as a bulky substituent which directed the income of the electrophile by the less hindered face of the enamine intermediate in the most stable pseudo-rrarw conformation. Alternatively, the formation of a hydrogen-bonded transition state was also proposed, in this case with the participation of the pseudo-cj5 enamine conformer. This second pathway was afterwards estimated to be the energetically most favored one by DFT calculations. ... 

Once in the modern organocatalysis era and with the mechanistic rationale for the iminium activation concept in hand, many different and more efficient methodologies have been developed for this particular reaction. For example, and still focused on the use of secondary amines as catalysts, imidazolidine 53a and proline-tetrazole 2a catalysts have been developed for the conjugate addition of malonates to acyclic enones (Scheme 3.17). For the 53a-catalyzed reaction, this proceeded well in terms of yields and enantioselectivities for a wide range of differently substituted arylideneacetones and for cyclohexenone but yields tend to decrease when more bulky substituents were placed around the carbonyl moiety. Importantly, the enantioselectivity of the reaction was very dependent upon the nature of the malonate reagent, observing that dibenzyl malonate and diethylmalonate furnished the best results. The most... 

Scheme 3.21 Enantioselective Michael addition of nitroalkanes to acyclic enones catalyzed by imidazolidines 53a and 53c, proline tetrazole 2a and amine-thiourea ent-37b.

The TIPS-protected L-prolinol derivative A (see Chapter 8) gave superior enantioinduction however, only 44% enantiomeric excess was still obtainable. Tetrazole-derived catalyst B (see Chapter 9) gave the highest yield (98% yield). Figure 5.9 illustrates the difference in reactivity and enantioselectivities between L-proline, and proline-derived catalysts A and B. 

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

Proline-derived tetrazole 5a was used for the reaction of nitrosobenzene with a-branched aldehydes. Selective formation of an a-hydroxyamination product over an a-amino>ylation product was observed by Kim and Park. Remarkably, N- vs. O- addition selectivity was observed for a,a-disubstituted aldehydes however, the enantioselectivities were only moderate (Scheme 9.45). 

Remarkably, no reaction occurred when proline, hydroxyproline or proline-tetrazole that did not exhibit surfactant properties were employed as organocatalysts in the presence of water. 

In 2008 Brimble and coworkers examined the effect of a-substitution in proline-based catalysts for the asymmetric aldol addition of acetone to aromatic aldehydes. In the benchmark aldol reaction between acetone and p-nitro-benzaldehyde they observed a remarkable improvement of stereoselectivity using (5 )-a-methyl-tetrazole 9, albeit with longer reaction times caused by the a-geminal disubstitution. Surprisingly 7a afforded a completely racemic product (Scheme 11.7). Using 9 the scope of this reaction was extended efficiently to several other aromatic aldehydes with excellent enantioselectivities (enantiomeric excess — 70-91%). 

---