Proline scheme

Hydride reduction of imine chelates such as (92) offers a synthetic route to a-amino acids, as demonstrated for cyclopropyl glycine and proline (Scheme 44).214... 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

However, a difference between both catalytic cycles can be seen in the reaction sequence for the formation of the enamines which are key intermediates of these aldol reactions. In case of the aldolase of type I a primary amino function of the enzyme is used for the direct formation of a neutral imine (la), while the enamine synthesis proceeds through a positive iminium system (lb) when starting from L-proline (Scheme 3). In this connection, inves-... 

It is well-known that catalytic amounts of aldehyde can induce racemization of a-amino acids through the reversible formation of Schiff bases.61 Combination of this technology with a classic resolution leads to an elegant asymmetric transformation of L-proline to D-proline (Scheme 6.8).62 63 When L-proline is heated with one equivalent of D-tartaric acid and a catalytic amount of n-butyraldehyde in butyric acid, it first racemizes as a result of the reversible formation of the proline-butyraldehyde Schiff base. The newly generated D-proline forms an insoluble salt with D-tartaric acid and precipitates out of the solution, whereas the soluble L-proline is continuously being racemized. The net effect is the continuous transformation of the soluble L-proline to the insoluble D-proline-D-tartaric acid complex, resulting in near-complete conversion. Treatment of the D-proline-D-tartaric acid complex with concentrated ammonia in methanol liberates the D-proline (16) (99% ee, with 80-90% overall yield from L-proline). This is a typical example of a dynamic resolution where L-proline is completely converted to D-proline with simultaneous in situ racemization. As far as the process is concerned, this is an ideal case because no extra step is required for recycle and racemization of the undesired enantiomer and a 100% chemical yield is achievable. The only drawback of this process is the use of stoichiometric amount of D-tartaric acid, which is the unnatural form of tartaric acid and is relatively expensive. Fortunately, more than 90% of the D-tartaric acid is recovered at the end of the process as the diammonium salt that can be recycled after conversion to the free acid.64... 

Like their ubiquitous 0(O-acetal relatives, N, 0-acetals can exceed the narrow bounds of passive protection and participate in synthetic operations of far greater significance. Wc will illustrate the point by the enantioselective a-alkylation of proline [Scheme 8.163]357 360 without the use of a chiral auxiliary. The procedure is another example of the self-regeneration of stereocentres and begins... 

The Sn(OTf)2-based chiral promoter system enables highly selective synthesis of both enantiomers of the aldol adducts by using similar types of chiral diamines derived from L-proline (Scheme 10.47). Diamines 50d and 50h are highly effective chiral sources for the synthesis of (2S,3K) and 2R,3S) adducts, respectively, from 52a [135]. In the aldol reaction of 52b, diamines 50f and 50g realize the selective synthesis of both enantiomers of the syn adducts [136]. The sense of diastereoselectivity can also be controlled by choice of the diamine ligands. The use of 50 g... 

A variation of this procedure has been used to obtain cyclodopa 5-<9-glucoside 128 from betanin 119 by base catalysed exchange with excess proline (Scheme 27) (84HCA1348). The glycoside is A-formylated (128- -129) upon standing in dilute formic acid solution. Other A-acylation reactions have been discussed in Section IllB (Scheme 20). 

The 5-mercaptomethylproline residue is one of such devices used for promoting intramolecular NS acyl shift reactions (Scheme 10a) [66]. In an aqueous solution containing MPA, peptide 34a is transformed into the thioester of MPA. This reaction is promoted by microwave irradiation. The thiazolidine structure can substitute for proline (Scheme 10b) [67]. This thiazolidine ring is constructed from a cysteine residue on the solid support, which simplifies the preparation of the thioester precursor. 

Use of cyclic amino acids instead of sarcosine to generate the corresponding dipole as well as the subsequent [3+2]-cycloaddition allowed to obtain condensed isoindoles [135]. Thus, tricyclic derivatives 173 were obtained in the case of proline (Scheme 84). 

By employing arylsulfonyl groups as suitable leaving groups, a highly stabilised carbocation could be generated using potassium fluoride supported on alumina, which then allowed for easy interception by the thus-formed nucleophilie enamine intermediate from the aldehyde and L-proline (Scheme 5.24). 

This reaction has been nsed to good effect over time. For example, Oshima, Shibasaki and co-workers synthesized (H-)-wortmannin 66, using L-phenylalanine instead of L-proline (Scheme 1.14) [15]. 

Aryl and vinyl azides can also be accessed in one step from the corresponding halides or triflates via a copper-catalyzed reaction with sodium azide in the presence of a catalytic amount of L-proline (Scheme 7.5C) [104]. In this fashion, a range of 1,4-disubstituted 1,2,3-triazoles can be prepared in excellent yields [105-107]. Anilines can also be converted to aryl azides by the reaction with tert-butyl nitrite and azidotrimethylsilane [108]. The resulting azides can be submitted to the CuAAC conditions without isolation, furnishing triazole products in excellent yields. Microwave heating further improves both reactions, significantly reducing reaction time [56, 62]. 

It is also interesting to note that -methylproline residues can be found in several peptide antibiotics such as bottromycin, scytonemin A, roseotoxin B in addition to several members of the paraherquamide family. Arigoni and Kellen-berger [41 ] have recently shown that the methyl group in the )3-methylproline in bottromycin, a metabolite of Streptomyces bottropenis, is derived from S-adeno-sylmethionine via methylation of proline (Scheme 19) and have proposed a radical mechanism for this reaction. 

A copolymer bearing proline and permethylated p-CD was used as catalyst in aldol condensation [23]. The linear copolymer bearing both pendant permethylated p-CD and proline groups was designed on the basis that the hydrophobic cavity of the CDs could approach the substrates close to the proline that acted as catalyst through host-guest interactions. The synthesis of the CD monomer was carried out by a copper-catalyzed azide-alkyne cycloaddition. The CD monomer was then polymerized with a protected hydroxyproline methacrylate to give the linear polymer with a monomer ratio proline/CD of 4.The Me-p-CD-Pro polymer was subsequently obtained after acid deprotection of proline (Scheme 2.9). 

Solar light is of no use for the above reaction, because anisoles do not absorb solar light, but the related anilines absorb and react in a fully analogous way (Scheme 12.3) [13]. In general, the abovementioned insensitivity to the medium makes possible a green choice [14]. Examples are solvent-free reactions (see the photooxygenation of neat benzene by water in Scheme 12.4 [15]), solid-state processes (see the cyclization of the carboxylate 4 that occurs with high enantiomeric excess from the salt with proline. Scheme 12.5 [16]), and reaction in water or... 

On the other hand, a number of asymmetric aldol reactions have been performed in the last year in the presence of variously substituted prolines as the organocatalysts. As an example, Zhao et al. reported excellent results for the cross-aldol reaction of cyclohexanone with p,y-unsaturated keto esters catalysed by a tra i-siloxy-L-proline (Scheme 2.3). This practical and highly efficient protocol could be extended to other ketones, albeit with lower enantioselectivities (<93% ee). 

Whereas DHAP-aldolase catalyzed aldol reactions have been thoroughly investigated [2-12], the use of pyruvate-aldolases is still in its infancy [39,40]. As the first chemical synthetic equivalents of PEP, which are able to transfer the pyruvic acid d -synthon (boxed), we have synthesized chiral pyravate hydra-zones from simple chemicals and (S)-proline (scheme 11). 

Transamidation of primary amides (10) by amines (11) may be carried out highly efficiently by heating equimolar amounts of each in the presence of 10mol% L-proline under solvent-free conditions (Scheme 4). In the proposed mechanism, L-proline condenses with an amide to form intermediate (A), which undergoes nucleophilic addition of an amine to generate a TI (B), loss of ammonia from which yields intermediate (C). In the final step, hydrolysis yields the transamidation product and regenerates L-proline (Scheme 5). ... 

Mac Millan and coworkers reported a multicatalytic approach by using a catalyst combination of imidazolidinone 8 and proline (Scheme 12.10). The cycle-specific Friedel-Crafts alkylation-amination of enals was studied with different nucleophilic components. For instance, the reaction of 1-methylindole as a Jt-nucleophile with the catalyst combination containing L-Pro (20 mol%) and 8 (10 mol%) provided the iyn-1,2-aryl amination adduct 23 with excellent yield (94%) and stereocontrol (syn/anti 14 1, ee 99%). Access to the corresponding anti isomer 24 was achieved by... 

In the same year Mosse and Alexakis [34] reported microwave-assisted asymmetric aldol reactions of acetone and various aromatic aldehydes catalyzed by proline (Scheme 21.12). In the model reaction, under microwave irradiation with simultaneous air-cooUng (25 °C) after 15 min the aldol product was obtained in 68% yield and with moderate enantioselectivity (74% ee). In comparison, the reaction without MW required 4h at room temperature to afford the same yield and selectivity. Comparing the yields and enantioselectivities of the product obtained... 

Bolm [59-61] applied ball-milling to an asymmetric solvent-free aldol reaction catalyzed by L-proline (Scheme 21.27). Especially, reactions of cyclohexanone (1.1 equiv) and various crystalline aromatic aldehydes were studied under the ballmilling conditions (250-400 rpm) at room temperature. To evaluate the effect of the mechanochemical technique, comparative studies using conventional stirring were carried out for each reaction. 

In contrast to the early report of intramolecular desymmetrization reactions [6], the intramolecular ring-closing reactions of achiral substrates via enamine catalysis were not disclosed until the beginning of the twenty-first century. In 2003, list reported the first highly stereoselective intramolecular aldol reaction of achiral dicarbonyl compounds. Cyclic aldol products 6a-< were delivered from heptanedials 5 with excellent diastereo- and enantioselectivity by the catalysis of L-proline (Scheme 36.2). The cyclization of ketoaldehyde 7 afforded alcohol 8 as a 2 1 diastereomeric mixture but with 99% ee. This strategy could provide P hydroxyl carbonyl derivatives that are of potential applications in organic synthesis [7aj. 

Very recently, Zhu and Cheng reported an organocatalytic Michael-type addition of phosphorus ylides 93 to a,(i-unsaturated ketones 94 using a chiral dual organo-catalyst system composed of 9-amino-(9-deoxy)-epi-quinine with Boc-L-proline (Scheme 43.20) [31]. The Michael-type/Wittig reactions proceeded smoothly to provide chiral a-methylene-6-ketoesters 95 with good to excellent enantioselectivi-ties (up to 95% ee). 

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