Prolines asymmetric induction

Comparison witli tlie Hajos-Parrisb asymmetric version of tlie Robinson annulation [81] iSdieme 7.25iaj) shows tlie following distinct differences between tlie two metliods. Firstly, tlie cydoalkenone in tlie CuiOTf)2/ligand 18-catalyzed procedure is tlie Midiael acceptor, whereas tlie cydoalkanone is tlie Midiad donor in tlie proline-mediated annulation. Secondly, tlie asymmetric induction occurs in tlie 1,4-addition step in tlie new metliod, in contrast to tlie asymmetric aldol-cydization in tlie Hajos-Parrisb procedure. 

Laxmi, Y.R.S. Iyengar, D.S. Synf/i. Commun., 1997,27,1731 (addition of L-proline to this reaction leads to moderate asymmetric induction). 

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). 

Reactions of the sulfonylsulfines 56 (e.g. R1 = R2 = Bn R1 — Me, R2 — Ph R1 — CPh3, R2 = ph etc.) derived from (S)-proline with 2,3-dimethyl-l,3-butadiene afford dihy-drothiopyran S-oxides 57 with asymmetric induction of up to 40% (equation 38)34. Methyl cyanodithioformate 58 is a very reactive dienophile with cyclopentadiene it forms a mixture of 40 parts of the endo-adduct 59 and 60 parts of the exo-isomer 60 (equation 39)35. 

Comparison with the Hajos-Parrish asymmetric version of the Robinson annulation [81] (Scheme 7.25(a)) shows the following distinct differences between the two methods. Firstly, the cycloalkenone in the Cu(OTf)2/ligand 18-catalyzed procedure is the Michael acceptor, whereas the cycloalkanone is the Michael donor in the proline-mediated annulation. Secondly, the asymmetric induction occurs in the 1,4-addition step in the new method, in contrast to the asymmetric aldol-cyclization in the Hajos-Parrish procedure. 

These compounds derived from 3-acetylthiazolidine-2-thione are very versatile chiral materials, capable of being transformed into various synthetic intermediates as previously demonstrated (30). Furthermore, in the stannous enolate mediated aldol-type reactions of 3-(2-benzyloxyacetyl)thiazolidine-2-thione, the stereochemical course of the reaction is dramatically altered by the addition of TMEDA as a ligand. High asymmetric induction is also achieved by the addition of a chiral diamine derived from (S)-proline (31). 

Rh2(S-TBSP)4 8 and Rh2(S-DOSP)4 9 (Tab. 14.3) [40, 45]. A very unusual feature of the prolinate-catalyzed cyclopropanations is that the reactions proceed with much higher asymmetric induction when hydrocarbon solvents are used instead of dichloromethane [40, 45]. Room-temperature cyclopropanations of styrene with Rh2(S-TBSP) or Rli2(S-D0SP)4 typically occur with 90-92% enantioselectivity, while the Rh2(S-DOSP)4-cata-lyzed reaction at -78°C occurs in 98% enantiomeric excess (Tab. 14.3) [40]. The rhodium prolinate catalysts are very easy to handle, being stable to air, heat, and moisture although it has been reported that the enantioselectivity can decrease if the cyclopropanation is conducted in wet solvents [46]. 

Fig. 14.3 Predictive models for asymmetric induction by (a) (R)-panto-lactone as a chiral auxiliary (b) (S)-prolinate dirhodium catalysts...

An organocatalytic asymmetric hydroxylation was developed using spiro-Meldrum s acid derivatives, 20mol% proline, and nitrosobenzene. In fact, the heterocyclic moiety was necessary for a high-yielding asymmetric induction (Equation 67) <20050L1577, 2006OBC2685>. 

Seebach and Naef1961 generated chiral enolates with asymmetric induction from a-heterosubstituted carboxylic acids. Reactions of these enolates with alkyl halides were found to be highly diastereoselective. Thus, the overall enantioselective a-alkyla-tion of chiral, non-racemic a-heterosubstituted carboxylic acids was realized. No external chiral auxiliary was necessary in order to produce the a-alkylated target molecules. Thus, (S)-proline was refluxed in a pentane solution of pivalaldehyde in the presence of an acid catalyst, with azeotropic removal of water. (197) was isolated as a single diastereomer by distillation. The enolate generated from (197) was allylated and produced (198) with ad.s. value >98 %. The substitution (197) ->(198) probably takes place with retention of configuration 196>. 

The asymmetric induction in the formation of (231) proceeds via a bromonium ion 231c). Denomination of (231a) with tri-n-butyltin hydride followed by saponification gave the chiral a-hydroxycarboxylic acid (232) in high optical purity. (S)-proline was recovered for recycling. 

Imidazolines (245) have been prepared from (S)-alanine and (S)-proline. Upon hydrolysis (R)-alanine was obtained. This result can be explained in terms of epimeri-zation and stereoselective protonation with asymmetric induction by the chiral center originating from (S)-proline246). 

If, in the above sequence, the (S)-proline is replaced by (S)-Phe or (5)-Ala, then the resulting asymmetric induction is considerably diminished. 

The asymmetric halolactonization reactions of unsaturated L-proline amides, developed by Terashima and coworkers,184 has been extended to a-alkyl acrylic acid derivatives (equation 75 and Table 21).185 This allows for the synthesis of either enantiomer of an a-methyl-a-hydroxy acid using L-proline as the auxiliary. Less successful approaches to asymmetric induction with a chiral auxiliary include iodolac-... 

Asymmetric induction in intramolecular C-H insertion reactions was first reported by McKervey and co-workers [53], who used chiral Rh(II) prolinate 17a (Eq. 5.24). Although enantiocontrol was low, this report established the feasibility of the methodology and left open advances that were subsequently made by Ikegami and Hashimoto, who were able to convert a-diazo-p-ketoester 47 into cyclopentanone 48 with 18a (Eq. 5.25) with 32-76% ee, dependent on the substituent Z and the size of the ester alkyl group [54,116],... 

The reaction of iV-benzyloxycarbonyl L-proline acid chlorides 134 with imine 135 in the presence of triethylamine, at room temperature, gave the corresponding spiro-(3-lactams 136, 137 as a 1 1 mixture of diastereoisomers, which were separated by column chromatography. The Staudinger reaction proceeds with complete stereoselectivity with a cis relative disposition of the pyrrolidine nitrogen and the phenyl group, but no asymmetric induction was observed. However, very... 

The hydrogenation of isophorone and acetophenone in the presence of (S )-proline shows some similarities. The effect of Pd-C-(5 )-prohne system is based on the addition reaction of the reactants and (S)-proline in solution and on the chemoselectivity of Pd. Both hydrogenations should be termed diastereoselective rather than enantioselective, since the asymmetric induction takes place in the adduct molecules. 

A series of chiral (3i ,5 RHlihvdroxypiperidine derivatives have been conveniently prepared from trans -4-hvdrox v- r.-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal.110 The compound (31) has been found to show the best asymmetric induction in promoting the addition of Et2Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee. 

The early phosphoramides 8 and 9 (Fig. 7.1), developed by Denmark [22], exhibited modest enantioselectivity in the allylation reaction (Scheme 7.1 and Table 7.1), but played an important role in the mechanistic elucidation and development of the second generation of catalysts (vide infra). The proline-derived phosphoramide 10 proved more selective (Table 7.1, entry 2) [14c, 15c], but its preparation is hampered by the fact that, unlike with 8 and 9, its phosphorus atom is stereogenic, so that two diastereoisomers are formed and need to be separated. Phosphoramide 10 has been reported to give higher asymmetric induction than its diastereoisomer (entry 2) [22f ]. However, the results are further affected by the variation of the N-substituents generally, the sense of asymmetric indue-... 

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). 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines52-54. For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%52. 

For a review (in German) on asymmetric induction using proline derivatives, see S. Blechert, Nachr. Chenu, Tech. Lab., 1979,27, 768. 

A striking solvent effect was observed in the reduction of a chiral a-keto amide, C6H5-CO-CO-NR2 (NR2 = (5)-proline methyl ester), with sodium tetrahy-dridoborate, leading to mandelic acid after hydrolysis [704]. When the a-keto amide was reduced in pure tetrahydrofuran or methanol, the resulting enantiomeric excess of (5)-mandelic acid produced was 36% and 4%, respectively. However, when a tetrahydrofuran/methanol (99 1 cL/L) solvent mixture was used, the enantiomeric excess increased to 64% ( ). In other solvent mixtures, a catalytic amount of a protic solvent (CH3OH or H2O) was found to be necessary for good asymmetric induction [704]. 

In this chapter, we present the contributions of computational chemistry toward understanding the mechanism and chemistry for three reactions involving nucleophilic attack. The 8 2 reaction, with emphasis on the gas versus solution phase, is presented first Next we describe the critical contribution that computational chemists made in developing the theory of asymmetric induction at carbonyl and vinyl compounds. The chapter concludes with a discussion on the collaborative efforts of synthetic and computational chemists in developing organic catalysts, especially proline and proline-related molecules, for the aldol, Mannich and Michael reaction, and other related reactions. 

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