Synthesis of proline derivatives

By using a three component 1,3-dipolar cycloaddition reaction, Hamper et al. developed a solid-phase synthesis of highly substituted pyrrolidines via resin-bound azomethine ylides. 

2-Arylquinoline-4-carboxylic acids and derivatives were shown to possess a wide variety of biological effects as antimalarial, antimicrobial, antitumor, antioxidants and cardiovascular agents. In addition, other derivatives have recently been shown to be potent tachykinin NK3 receptor antagonist or to exhibit analgesic activity. O  

Although electron-withdrawing groups in the aldehyde building-block improved the overall yield, the reaction proceeded well for benzaldehyde. Furthermore there was no significant effect on the cyclisation by varying the amino acid employed. 

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Proline has been often used in reactions with aldehydes to form 1-oxo perhydropyrrolo[l,2-f]oxazole structures <1998J(P1)3777, 2004PNA5839>. These compounds were used for the asymmetric synthesis of proline derivatives which are present in natural products or analogs (Scheme 49) <2005T10018, 2005TA2075, 2006JOC97>. 

Thiruvazhi et al. [112] have shown interest in the area of (3-tum mimetics and the synthetic application of d- and L-proline for asymmetric synthesis of proline-derived spiro-(3-lactams. It has been shown that the asymmetric Staudinger reaction of optically active acid chloride of d- and L-proline with achiral imines is impossible due to the loss of stereochemistry at C-2. The authors have developed a strategy in which a chiral group at C-4 of the acid chloride of proline directs the stereoselectivity of the reaction and is sacrificed later to obtain optically active spiro-(3-lactams (Scheme 38). 

Scheme 38 Asymmetric synthesis of proline-derived spiro-fS-lactams...

The synthesis of proline-fused heterocyclic systems by 1,3-dipolar cycloaddition has been well-established in solution-phase synthesis (Scheme 14) [42]. It is usually performed as a one-pot, three-component reaction of a dipo-larophile with an in situ prepared azomethine ylide. Perfluoroalkanesulfonyl protected hydroxybenzaldehydes [43] or fluorous alcohol protected amino esters [44] have been developed as two different fluorous components for the synthesis of proline derivatives 11 and 12. 

Scheme 1 Asymmetric synthesis of proline derivatives via a Norrish-Yang photocycliza-tion...

Another example to illustrate the synthesis of proline derivatives 78 was published by Vicario and coworkers in 2013 [48]. Starting from aromatic aldehydes, diethyl malonate, and a,p-unsaturated aldehydes upon catalysis of unprotected diphenylprolinol, the synthesis of polysubstituted pyrrolidines was achieved in a one-pot condensation and [3+2] cycloaddition reaction in aqueous medium. 

This approach has been extended to cyclic 1,3-dicarbonyls for the synthesis of tetrahydrobenzopyrane derivatives, also known as tetrahydrochromenes, which have attracted much attention due to their wide range of biological properties. Thus, a mixture of an aromatic aldehyde, dimedone, and malonitrile in aqueous media catalyzed either by (5)-proline [123] or tetramethylammoniura hydroxide (TMAH) [124] gave the bicyclic heterocycle in excellent yields (Scheme 35). 

Murahashi and co-workers (49) extensively studied the synthesis of nitrones such as 29 by a decarboxylative oxidation of proline derivatives (Scheme 12.12). However, these nitrones were primarily used in nucleophilic addition reactions rather than 1,3-dipolar cycloadditions. Others have synthesized cyclic nitrones 30 and 31 having a chiral center adjacent to the nitrogen atom (50,51). Saito and co-workers (51) applied nitrone 31 in reactions with fumaric and maleic acid... 

More recently, Tardella and co-workers disclosed the use of this reagent in the synthesis of Af-(ethoxycarbonyl)-a-amino ketones from enamines and nitrene 18 [12b]. Their attempts to obtain asymmetric induction started with the use of proline-derived optically active enamines of cyclohexanone. Slow addition of sulfonyl-oxycarbamate 6e (1 equiv.) to a stirred solution of the enamine 19 and triethylamine (1 equiv.) in dichloromethane at room temperature, followed by work-up with petroleum ether and silica gel chromatographic purification afforded the aminated product 20 in low yield and good enantiomeric excess [12c] (Scheme 8). 

L-Proline catalyzes the aldol reaction. This approach has been applied to the synthesis of carbohydrate derivatives as illustrated by the glucose derivative 7 (Fig. 11) (237). The three-component Mannich reaction can be used to prepare p-amino and p-amino a-hydroxy carbonyl compounds in a single step (Fig. 12) (233). As with other types of catalysts, organocatalysts can be immobilized to aid recovery (253). 

Diastereoselective fluoro-functionalization of proline derivatives produces fluorinated prolines. Both enantiomerically pure 4-trifluoromethyl and 4-difluoromethyl prolines 268 and 270 have been prepared (see Scheme 9.57) [85]. The key reaction for the stereo-controlled synthesis is diastereoselective Pd-catalyzed hydrogenation of 267 and 269. 

Various substituted benzimidazoles have been synthesized in very good yields in solvent-free conditions from 1,2-diaminobenzene and aldehydes in the presence of titanium(IV) chloride as a catalyst. The method is applicable to most aromatic, unsaturated and aliphatic aldehydes and to substituted 1,2-diaminobenzenes without significant differences [14]. Several other catalysts, namely iodine [15], hydrogen peroxide [16], zirconyl(IV) chloride [17], boron trifluoride diethyl etherate [18], ytterbium perfluorooctane sulfonates [19,20], zeolite [11,21], and L-proline [22], have been effectively used for the synthesis of benzimidazole derivatives. 

Joulli6 ef have developed a totally novel and very elegant approach to the synthesis of proline peptides that is based on the Ugi reaction of pyrroline derivatives. 

Application of aza-annulation with cyclic enamino esters was reported in the synthesis of angiotensin converting enzyme inhibitor A58365A (323, Scheme 27).90 Aza-annulation of proline derivative 319, which was obtained in 4 steps from L-pyroglutamic acid, with a-methyleneglutaric anhydride (320) led to the formation of indolizidinone 321 as a mixture of diastereomers. Esterification followed by oxidation with DDQ gave 322, which was converted in 4 steps to the desired target 323. 

Proline benzyl ester 3 is the starting material for a variety of A -substituted derivatives formed by A-acylation with unsaturated acids, which are useful chiral dienophiles for enantioselective Diels-Alder reactions (Section D. 1.6.1.1.1.). The synthesis of these derivatives, e.g., (S)-6 or (S)-7 is conveniently achieved by A-acylation of the hydrochloride or tosylate of the benzyl ester (the allyl ester may also be used) of proline with triethylamine/4-(dimethyl-amino)pyridine5. 

The synthesis of various proline derivatives has received attention this year. A route to proline itself from pyrrolidine in 45% overall yield has been reported, which appears to be an improvement on previous multistage methods.A one-pot synthesis of racemic 4-hydroxyproline in 30—40% yield from glyoxal and oxaloacetic acid has been developed, and a total synthesis of all four dias-tereoisomers of 3-hydroxy-5-methylproline has been achieved. An asymmetric synthesis of prolines is by addition of malonate carbanions to chiral aziridines derived from amino-acids. ... 

Gurjar and co-workers prepared several novel carbohydrate-based spirocycles and a spirocyclic proline derivative for applications in peptide, nucleoside, and carbohydrate synthesis. Ring-closing metathesis of carbohydrate diene precursor 78 furnished the corresponding spirocycle 80 in 88% yield using a catalytic amount of 3 in dichloromethane. Reaction of proline derivative 79 under similar conditions gave the corresponding spirocyclic peptide 81 in 96% yield. 

Mori and Ban then reported a novel synthesis of benzodiazepine derivatives by Pd-catalyzed carbonylation of o-haloaniline derivatives 10, which was prepared from o-haloanilines 8 (Scheme 4) and amino acid derivatives 9. They succeeded in the total synthesis of many benzodiazepine antitumor aulibiotics. A toluene solution of o-bromoani-line derivative 10a, which was prepared from 2-hromo-4-methoxy-5-tosyloxyaniline and 4-hydroxy-/-proline, Pd(OAc>2, PPhs, and BU3N, was heated at 110 °C for 48 h under carbon monoxide (5 atm) to produce benzodiazepiue derivative 11a. Compound 11a was converted into 12, which was a key intermediate for the synthesis of anthramycin (ISa). Using a similar procedure, they succeeded iu the total synthesis of tomaymycin (13b), prothracarcin (13c),t pretomaymycin (13d),t neothramycin (13e)t and SEN 215 (13f). ... 

In a different approach to the synthesis of chromane derivatives, Penunal developed a three-component reaction between salicylaldehyde, malononitiile and indole in water using L-proline as the catalyst (Scheme 1.39). In the meehanism of this transformation, indole reacts readily via a Michael addition with a 2-imino-3-chromene-3-caibonitrile intermediate 73, generated from salicylaldehyde and malononitiile in water, to furnish compounds 74 [61],... 

A related method was applied to the synthesis of 18 isoxazolothiohydantoins (Scheme 11.51)/ Hydantoin formation was also applied to the release of proline derivatives that were obtained from the intramolecular cycloadditions of resin-bound azomethine ylides and alkenes. ... 

There is continued interest in chiral syntheses of pyrrolidines, piperidines, and related bicyclic systems. A review has appeared, in Russian, on the stereoselective synthesis of proline and pipecolic acid derivatives from sugars. The antifungal pyrrolidine (+)-preussin (74) has been made from the glucose-derived epoxide (73) as indicated in Scheme 16,58 whilst... 

Application of a proline-catalyzed intermolecular aldolization in the synthesis of carbohydrate derivatives. 

A highly stereoselective proline-catalyzed acetone aldol reaction has recently been used in the synthesis of sugar derivatives such as 141 (Scheme 4.28) [124]. 

A series of functionalized chromanes were generated from a C—H alkylation reaction between 1-naphthol and a series of a,p-unsaturated-a-keto esters (Scheme 2.22) [27]. The chemistry was carried out under very mild conditions using an organocatalyst and was remarkably insensitive to the electronic composition of the a-keto ester. Heteroaromatic examples were also successfully functionalized using this approach. The chemistry was successfully extended to 2-naphthol and excellent conversions (up to 90%), and high enantioselectivities were obtained (up to 96% ee). In related work, a simple proline derivative was also able to promote the asymmetric synthesis of chromane derivatives (Scheme 2.23) [28]. 

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