Pyrrolidine aldol reactions

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

The synthesis of the rare amino acid 3-hydroxy-4-methylproline (8)3 involves an aldol reaction of the oxazoiidinone 5 with methacrolein to provide the a-bromo-0-hydroxy adduct 6. Azide displacement and removal of the chiral auxiliary gives 7. On treatment with dicyclohexylborane, 7 undergoes hydroboration-cycloalkyl-ation to provide, after hydrolysis, the methyl ester hydrochloride (8) of (2S,3S,4S)-3-hydroxy-4-methylproline in >97% de. This cycloalkylation should be a useful route to cyclic amino acids as well as pyrrolidines. 

One way to achieve a higher stereoselectivity in these aldol reactions could obviously be the variation of the alkoxy group on the pyrrolidine sidechain of the chiral auxiliary. Thus, Enders and co-workers synthesized the SAMP-analogue (159). While acetone-SAMP-hydrazone leads to a (+)-[3-hydroxyketone in 47% e.e., the corres-... 

The catalytic cycles are, however, different in the reaction sequence for formation of the enamines which are key intermediates in these aldol reactions. With the type I aldolase a primary amino function of the enzyme is used for direct formation of a neutral imine (Ha) whereas starting from L-proline enamine synthesis proceeds via a positive iminium system (lib) (Scheme 6.23). In this respect, investigations by List et al. on the dependence of the catalytic potential on the type of amino acid are of particular interest. In these studies it has been shown that for catalytic activity the presence of a pyrrolidine ring (in L-proline (S)-37) and the carboxylic acid group is required [69]. 

Carefully matched acid and base catalysis has been used to select the pyrrolidine-p-nitrophenol combination as an efficient organocatalyst for direct aldol reactions.108... 

Hydroxyaldehydes, with an intervening quaternary centre, have been synthesized enantioselectively by direct aldol reactions of oqa-dialkylaldehydes with aromatic aldehydes, using a chiral bifunctional pyrrolidine sulfonamide organocatalyst.118... 

The six-membered transition-state is stabilized by hydrogen-bonding between the nitrogen of the imine and the carboxyl group of proline. Switching of the facial selectivity is disfavored, because of to steric repulsion between the PMP group of the imine and the pyrrolidine moiety of the enamine. This is opposite to similar direct asymmetric aldol reaction in which re-facial attack occurs [27, 30, 36]. 

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-... 

Aldol reactions. In the presence of these two promoters and in combination with the chiral diamine (S)-l-methyl-2-[(piperidinyl)methyl]pyrrolidine (13, 302),... 

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

Thiosalicylaldehydes afford chiral thiochromene-3-carbaldehydes 39 on reaction with a,P-unsaturated aldehydes catalysed by a chiral pyrrolidine silyl ether. Initial activation of the enal triggers sequential Michael and aldol reactions and dehydration completes the highly enantioselective synthesis <06JA10354, 06TL8547>. In a similar manner, cyclic enones afford cycloalkanone[ ]thiochromenes <06TL8679>. 

Tetrahydroxanthen-l-ones have been obtained through enantioselective domino oxa-Michael - aldol reactions between salicylaldehydes and cyclohexenones using a chiral pyrrolidine catalyst in the presence of 2-nitrobenzoic acid <07TL2181>. A similar approach using chiral 4-hydroxycyclohexenones and V-methylimidazole as catalyst leads to a diastereomeric mixture of the reduced xanthones (Scheme 40) <07S2175>. Dimeric... 

Use of fluorous pyrrolidine sulfonamides 5 for enantioselective aldol reactions and Michael additions are shown in Fignre 1.4. The aldol reaction of cyclohexanone and 4-nitrobenzaldehyde under 10 mol% of the catalyst gave product 6 in 90% yield with a 70% ee and a 2 1 syn/anti ratio. The catalyst can be recovered by F-SPE and reused up to 6 times without significant loss of catalytic activity. 

FIGURE 1.4 Fluorous pyrrolidine sulfonamide-catalyzed Michael addition and aldol reaction. 

In the reactions with the propionate derivatives, which provide synthetically useful a-methyl-/3-hydroxy ester derivatives, a combination of Sn(OTf)2, (5)-l-methyl-2-[(A(-l-naphthylamino)methyl]pyrrolidine, and Bu3Sn(OAc)2 gives better results (Eq. 20) [33,35]. The asymmetric aldol reactions proceed with higher enantioselectivity and, in addition, the reactions proceed faster with Bu3Sn(OAc)2 as an additive than with BusSnE A wide variety of aldehydes including aliphatic, aromatic, and a,/3-unsatu-rated aldehydes can be used in this reaction, and the aldol adducts are always obtained in high yields with perfect syn selectivity the enantiomeric excesses of these syn adducts are > 98 %. 

Asymmetric synthesis of 1,2-diol derivatives based on asymmetric aldol reactions of a-alkoxy silyl enol ethers with aldehydes has been developed. The reaction of (Z)-2-benzyloxy-l-(5)-ethyl-l-trimethylsiloxyethene with benzaldehyde was conducted in dichloromethane at -78 °C with a chiral promoter consisting of Sn(OTf)2, (5)-l-ethyl-2-[(piperidin-l-yl)methyl]pyrrolidine, and Bu2Sn(OAc)2, to afford the corresponding aldol adduct in 83 % yield with 99 % anti preference. The enantiomeric excess of anti aldol is 96 % [38a]. In the aldol reaction of several kinds of aldehydes, e.g. aromatic,... 

With respect to the enol, this mechanism is similar to that of halogenation (12-4). A side reaction that is sometimes troublesome is further condensation, since the product of an aldol reaction is still an aldehyde or ketone. The aldol condensation of aldehydes has also been done using a mixture of pyrrolidine and benzoic acid. ... 

When 2-azidoaldehydes are used as substrates in the RAMA-catalyzed aldol reaction with dihydroxy acetone phosphate (DHAP), the azidoketones thus obtained can be reduced into the corresponding primary amines. Subsequent equilibration to imine intermediates, followed by reduction, generates the corresponding pyrrolidines (Scheme 13.16) [22,33]. 1,4-Dideoxy-1,4-imino-D-arabinitol 11 was prepared from azidoacetaldehyde. Both 2R,5R) and 2S,5R)-bis(hydroxymethyl)-(3R,4R)-dihydroxypyrrolidine (12 and 13) were derived from racemic 2-azido-3-hydroxypropanol. The aldol product resulting from kinetic control was converted into the (2R,2R) derivative 12, whereas the product resulting from thermodynamic control gave the... 

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]. 

However, despite the rapid design of news CILs, successful applications in synthesis remained elusive for some time. Only in the last 2-3 years have some significant results been obtained. Leitner and co-workers in 2006 reported a high enantiomeric excess (84% ee) by using a chiral anion containing ionic liquid for an aza-Baylis-Hillman reaction (Scheme 4.11), whereas CILs with an imidazolium or a benzimidazolium unit attached to (5)-pyrrolidine have been used with success as solvents or catalysts for asymmetric aldol reactions and Michael additions to nitroolefins (ee up to 99%). ... 

---