Proline nucleophilic addition reactions

Besides high effectiveness in the diastereoselective control of nucleophilic addition reactions, another major goal in the design of chiral auxiliaries is the use of readily available, chiral starting materials. The hexahydro-l//-pyrrolo[l,2-c]imidazole derivatives 9a-e are examples which use the inexpensive amino acid L-proline (7) as starting material. 

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... 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

Proline also is synthesized from glutamate 5-semialdehyde hy nonenzy-matic formation of a cyclic imine followed by enzymatic reduction of the C=N bond with NADH in a nucleophilic addition reaction. 

Basically, two different routes are conceivable for their asymmetric construction 1) nucleophilic substitution reaction with a fluoride anion and 2) electrophilic addition of fluoronium cations to activated or masked carbanions. First attempts on enantioselective nucleophilic fluorination date back to the pioneering work of Hann and Sampson [3]. In an ambitious dehydroxylation/fluorination sequence the authors reacted a racemic a-trimethylsiloxy ester with a half molar equivalent of an enantiomerically pure proline-derived aminofluorosulphurane in hope to achieve a kinetic resolution. Unfortunately, the fluorinated product was obtained without significant enantiomeric excess. 

S)-proline-catalyzed reaction using propionaldehyde as donor and the results showed that the imine reactivity was approximately sevenfold higher than that of the aldehyde [83]. Under basic conditions, it is generally accepted that nucleophilic addition to an aldehyde is typically faster than addition to an aldimine, but nucleophilic addition to an aldimine is faster than addition to an aldehyde when protonation of the imine nitrogen occurs [83]. In the (S)-proline-catalyzed three-component Mannich reactions in the absence of arylaldehyde, self-Mannich products were obtained with moderate to high diastereo- and enantioselectivities (Scheme 2.19) [71b, 82]. 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

This asymmetric Mannich reaction could also proceed by an enamine pathway because nucleophilic addition of the in situ-generated enamine would be faster to an imine than to an aldehyde. As shown in the Fig. 12.59, the reaction starts with enamine 34 activation of the cyclohexanone by the proline anion and an electrostatic interaction with the imidazolium moiety of the catalyst In a second pre-equilibrium, the aldehyde and aniline produce an imine. Then enamine-activated 35 reacts with the imine to form 35 via transition state A. The last step is a dehydration reaction to afford the corresponding product. The catalyst is regenerated in the subsequent step. 

Aldol additions of acetone (1) as a nucleophile to ketones without a-acidic protons are feasible. The proline-catalyzed aldol reaction between acetone (1) and 1-aryl-2,2,2-trifluoroethanone (128) led to tertiary alcohol 129 in good yield but with low stereoselectivity [146]. A proline-derived sulfonamide 130 performs much better (Table 3.10, entry 2). Kokotos prepared a prolinamide-thiourea catalyst 131, which under optimum conditions can be used in 2 mol%, even at 0°C (entry 3) [ 147], With proline, the reaction was completed within hours, while more stereoselective catalysts 130 and 131 required 2 days. So far, these are the catalysts of choice for this tran ormation [146-148]. 

As an efficient bifunctional catalyst, proline has been used as a Br0nsted acid in combination with a nucleophilic Lewis base catalyst in the asymmetric BH reaction. Miller and co-workers [119] disclosed that in the L-proline-catalyzed BH reaction of MVK and electron-deficient aldehydes the imidazole-tailed peptide 67 was an efficient co-catalyst. A matched/mismatched phenomenon of two chiral catalysts was observed in this reaction. Furthermore, Zhou and co-workers [120] synthesized various chiral amines and screened them as co-catalysts of L-proline in the BH reaction of MVK and aldehydes, revealing that chiral benzodiazepine 68 and aminoalcohol 69 were efficient catalysts. Interestingly, the intramolecular reaction shown in Scheme 9.34 could be directly catalyzed by L-proline in DMF solvent, while the addition of imidazole resulted in enhancement of the enantioselectivity with opposite configurational product [121]. A similar process was realized in the intramolecular reaction shown in Scheme 9.35 with 70 as co-catalyst of iV-methylimidazole. Moreover, Cordova and co-workers [122] reported in 2007 the first example of asymmetric aza-BH reaction between (3-mono- or disubstituted acroleins and aldimines. By utilizing L-proline as catalyst in combination with... 

For instance, 89 was converted into 90 in 96 % yield, which could be transformed into 91-93 by nucleophilic additions to the C=N-bond. The nitrile function of 92 can be hydrolyzed to the amino acid, and the olefmic moiety in 91-93 may be submitted to a manifold of addition reactions (Fig. 34). After N-protec-tion and 0-deprotection prolinols 91-93 can be oxidized to prolines. 

Another compound obtained from 3-deoxyosone via a relatively complex reaction is maltoxazine (VII in Formula 4.59), which has been identified in malt and beer. This compound could be formed from 3,4-dideoxyosone, which first undergoes a Streaker reaction with the secondary amino acid proline with decarboxylation to give the 1-pyrroline derivative (Formula 4.65). Enolization, formation of a five-membered carbocyclic compound and nucleophilic addition of the hydroxymethyl group to the pyrroline cation yields the tricyclic maltoxazine. In general, the formation of such carbocyclic compounds is favored in the presence of secondary amino acids like proline. 

By aiming at BRMs within MBFTs and organocatalysis, this section is limited to a small field of research. Nonetheless, the method is very productive, and the number of interesting examples extends far beyond the number that will be discussed in this section. Therefore, we will start, without further introduction, with the first example by Itoh and coworkers, who reported a proline-catalyzed asymmetric addition reaction for the synthesis of mf-dihydrocomynantheol in 2006 [6]. The reaction commences with activation of methyl vinyl ketone derivative 1 to form the intermediate enamine 4. Simultaneously, the acidic carboxyl group allows activation of the imine 2 and directs the newly formed nucleophile to add stereoselectively on iminium ion 5. The resulting o,p-unsaturated iminium is prone to diastereoselective cyclization by aza-Michael addition of the liberated secondary amine (Scheme 14.1). 

To expand the scope of C-based nucleophiles in asymmetric CDC reactions, organocatalysis was examined. Klussmann and co-workers reported a catalytic system consisting of VO(acac)2/TBHP and L-proline for cross-coupling between simple ketones and N-aryl THIQs. These two catalysts are considered to play independent roles. Although the proposed mechanism involves nucleophilic addition of chiral enamines to iminium ions formed oxidatively from THIQs. The level of asymmetric induction was low ( 17% ee). 

It is assumed that both reactions start with the formation of the imine of the acyclic structure of carbohydrates with proline. After this initial step, the cyanoacetate 86 dictates aKnoevenagel/Michael cascade, whereas by employment of isocyanoacetate 87 a nucleophilic addition of the carbon atom of the isocyano group and subsequent rearrangement reaction are observed. An explanation for this different behavior of the isostructural compounds (ethyl esters 86 and 87) depicted in Scheme 2.18 is given by the different sites of highest nucleophilicity as described by Mayr et al. [41]. These mechanistic considerations are depicted in Scheme 2.19. 

Polypropionate fragment 24 is obtained upon desulfurization (Raney nickel) of the corresponding thiane. It is interesting to note that addition of nucleophile to aldehyde ( )-21 shows exclusive Felkin diastereoface selectivity. One can assume that the transition state of the aforementioned transformation equals that predicted for proline-catalyzed aldol reactions between cyclohexanone... 

The first organocatalytic enanhoselective nucleophilic addition to a, ]3-unsaturated ketones was reported by Kawara and Taguchi in 1994 [9]. In this report they stated that chiral proline-derived ammonium hydroxides catalyzed the reaction between malonates and a,(3-unsaturated ketones in good yields and moderate enantioselectivities (up to 71%). 

The mechanisms of the reactions of the cluster Ru3(CO)i2 with halide ions, alkoxide ions and amines, all of which involve initial rapid nucleophilic addition at a carbonyl hgand, have been reviewed.In a related study, addition of 5-proline methylester or 5-methoxymethyl pyrrolidine to a carbonyl ligand of Ru3(CO)j2 has yielded chiral carbamoyl clusters of the type (84) R = C02Me or CH20Me, Eq. (16). Such chiral clusters may have potential as new enantioselective catalysts, as shown by the observation that cluster (84), R = CH20Me) catalyzes the isomerization of the prochiral allylic alcohol nerol to give the chiral aldehyde citronellal with an enantiomeric excess of 12%. 

The selectivity observed with hydroxyacetone (206) in proline-catalyzed aldol additions is particularly remarkable, as the scope includes a wide range of aldehydes to furnish a,/i-ketone diols such as 207 under mild conditions (Equation 19) [102]. The addition reactions of protected derivatives of a-hydrox) aldehydes as nucleophile coupling partners and aldehyde electrophiles in proline-catalyzed aldol reactions have recently been used to provide access to fragments that can be converted into a variety of carbohydrates [103). 

Two structurally unrelated immunosuppressant drugs, cyclosporin A and FK506, have been shown to bind to separate proteins, which have in common the ability to catalyse the interconversion (8) of the cis and trans rotamers of peptidyl-proline bonds of peptide substrates. A profound change in the conformation, and hence the shape and binding properties of the protein, may result. The mechanism of this isomerization appears, on the basis of recent work (Rosen et al., 1990 Van Duyne et al., 1993 Albers et al., 1990), to involve simple twisting about the amide bond, rather than such alternatives as conversion to a C-N single bond by addition of a nucleophile to C=0.y The proteins which catalyse the reaction may be... 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

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