Prolines as chiral auxiliary

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

The hetero-Diels-Alder reaction of chiral sulfines 24, bearing the relatively cheap (S)-proline as chiral auxiliary, with 2,3-dimethyl-l,3-butadiene (17) proceeds with low to moderate diastereoselectivity66. 

In one of the first reported stereoselective alkylation reactions [18], Yamada described the use of a methyl prolinate as chiral auxiliary in the methylation of a cyclohexanone-derived enamine (Fig. 3 reaction D).The low stereoselectivity of the reaction clearly depends on the possibility for the alkylation to occur on a different conformation of the enamine, namely the one in which the C-C double bond is transoid to the stereocenter, that thus cannot exert any useful stereocontrol. 

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). 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

The chiral auxiliaries anchored to the substrate, which is subjected to diastereoselective catalysis, is another factor that can control these reactions. These chiral auxiliaries should be easily removed after reduction without damaging the hydrogenated substrate. A representative example in this sense is given by Gallezot and coworkers [268], They used (-)mentoxyacetic acid and various (S)-proline derivates as chiral auxiliaries for the reduction of o-cresol and o-toluic acid on Rh/C. A successful use of proline derivates in asymmetric catalysis has also been reported by Harada and coworkers [269,270], The nature of the solvent only has a slight influence on the d.e. [271],... 

The methyl and benzyl esters of proline were also used as chiral auxiliaries in respective acrylamides, but the isoxazoline cycloadducts were obtained with only poor to modest stereoselectivity (189,190). The related indoline-2-carboxylic acid derivative 33, however, showed excellent ability to direct nitrile oxide attack, favoring one rotamer (Scheme 6.37), and thereby leading to 3-phenylisoxazoline-5-carboxamide... 

Asymmetric reduction of the double bond of the dehydroamino acid residue in 522 can be effected in different ways since the peptide moiety can act as a chiral auxiliary. Heterogeneous hydrogenations using a Pd/C catalyst are the most frequently used conditions. Among the different amino acids evaluated as chiral auxiliaries, proline is the auxiliary of choice and has led to the best diastereodiffer-... 

The (R)- and (S)-enantiomers of (E)-4.6-dimethyl-6-octene-3-one (147), a defense substance of spiders (known commonly as daddy longlegs Leiobunum vittatum and L. calcar) were recently synthesized by Enders and Baus 163> using the (R)-proline derivative RAMP and the (S)-proline derivative SAMP (137) as chiral auxiliary, respectively. (S)- and (R)-enantiomers of (147) have been obtained in an overall chemical yield of 70% and in very high stereoselectivities of 95% e.e., respectively. 

Enders and Lotter174) developed an asymmetric synthesis of a-hydroxyketones and vicinal diols using the (S)-proline derivative (S)-l-formyl-2-methoxymethyl-pyrrolidine as chiral auxiliary. However, the a-hydroxyketones and vicinal diols, respectively, were only obtained with low stereoselectivity. 

Kolb and Barth 229) synthesized oc-substituted optically active amines or amino acids (223). Again the authors employed a derivative of naturally occurring (S)-proline, namely (—)-(S)-l-dimethoxymethyl-2-methoxymethyl-pyrrolidine (221) as chiral auxiliary agent. The metalation of the amidines (160) leads to azaallyl anions homologous with (222). After alkylation and hydrolysis, the desired a-substituted amines and amino acids, respectively, are obtained with some stereoselectivity. 

In the total synthesis of an anthracycline antibiotic, the key step was an asymmetric halolactonization reaction. The corresponding bromolactones were formed with high stereoselectivity (d.s. > 90%). (S)-Proline was used as chiral auxiliary. 

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-... 

Chiral Amines with C2 Symmetry, trans-2,5-Dimethylpyrrolidine (1) was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis. Since that time a number of related systems have been developed including the title compound (2) and (4). These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis, the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of tranf-N-benzylpyrrolidine-2,5-dicarboxylic acid, although other preparations have been... 

A method for highly efficient asymmetric cyclopropanation with control of both relative and absolute stereochemistry uses vinyldiazomethanes and inexpensive a-hydroxy esters as chiral auxiliaries . This method was also applied for stereoselective preparation of dihydroazulenes. A further improvement of this approach involves an enantioselective construction of seven-membered carbocycies (540) by incorporating an initial asymmetric cyclopropanation step into the tandem cyclopropanation-Cope rearrangement process using rhodium(II)-(5)-N-[p-(tert-butyl)phenylsulfonyl]prolinate [Rlni — TBSP)4] 539 as a chiral catalyst (equation 212)- . ... 

In 2001, Tungler and coworkers described the diastereoselective hydrogenation of N (1 methylpyrrole 2 acetyl) (S) proline methyl ester (32) using the Rh/C as cata lyst [40]. By introducing (S) proline moiety as chiral auxiliary, high asymmetric induction was obtained. When 32 was subjected to 5% Rh/C catalyst in methanol with 20 bar H2, the reduced product 33 was obtained with full conversion and 95% de. This substrate induced asymmetric reduction and was effective only to (2 pyrrolyl) acetic acid derivatives (Scheme 10.30). 

Two year later, Pinel group used (S) proline and (S) pyroglutamic esters as chiral auxiliaries for the diastereoselective hydrogenation of 2 methylnicotinic acid with up to 35% de [50]. They tried to improve diastereoselectivity of these reactions, but no better result was obtained (Scheme 10.37). 

A high degree of stereocontrol can be obtained with the appropriate substituents on the nitrogen3Sa. Intramolecular cycloaddition of the keteniminium salt derived from 13 gives cyclobu-tanone 14 with only 27% ee. The low enantiomeric excess is probably due to the formation of two diastereomeric keteniminium salts. The use of proline derivatives as chiral auxiliaries is probably limited to keteniminium salts bearing two identical substituents at C-2. If a chiral auxiliary with C2 symmetry is used only one keteniminium salt can be formed, so that adducts with high enantiomeric excess should be formed. 

Aldol reaction with L-proline as catalyst has been extended to a-ketols thereby generating anti-diols. Transition state 48 is consistent with the results of aldol condensation catalyzed by Et2Zn-Ph,PS in the presence of a bisprolinol. a-Amino acid derived imi-dazolidinones serve as chiral auxiliaries in the same manner as the corresponding oxa-zolidinones. In employing 4-f-butylthiazolidin-2-thione, the presence of one or two equiv of a base leads to syn products of opposite enantiomeric series. 

Waldmann has looked at the possibility of using proline esters as chiral auxiliaries for aqueous Diels-Alder reactions (Table 1.7) [53] ... 

Waldmann, H. (1990) Proline benzyl ester as chiral auxiliary in Barbier-type reactions in aqueous solutions, Synlett, 627-8. 

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. 

As shown in scheme 1, (S)-amide 2 (ref. 4) obtained from ethyl ester of (S)-proline, chiral auxiliary and 2-substituted-2-propenoic acids 1 are bromolactonized with N-bromosuccinimide (NBS)-DMF, followed by hydrolysis with 6N-HC1 to afford (S)-4. The results are summarized in Table 1. 

Several reviews and research papers discussing the application and extension of this method have appeared.40 For example, Weber et al.41 reported an interesting result in which cerium acted as a counterion in the modified proline auxiliary (SAMEMP 40) for selective addition of organocerium reagents to hydrazones. The initial adduct was trapped with either methyl or benzyl chloro-formate to afford the stable /V-aminocarbonatc 41 (Scheme 2-24). From this example readers can see that this proline chiral auxiliary can be used not only for a-alkylation but also for nucleophilic addition, which is discussed in detail later. 

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

The asymmetric [3 + 4] cycloaddition is readily achieved using chiral auxiliaries or catalysts [16]. The efficiency of the chiral auxiliary approach is illustrated in the [3-1-4] cycloaddition with cyclopentadiene. The vinyldiazoacetate 6, with (T)-pantolactone as the chiral auxiliary, generated the bicyclo[3.2.1]octadiene 75 in 87% yield and 76% dia-stereomeric excess (Eq. 10) [82]. Alternatively, the chiral rhodium prolinate Rh2(S-DOSP)4-catalyzed reaction of 4 generated the bicyclo[3.2.1]octadiene 76 in 77% yield and with 93% enantiomeric excess (Eq. 11) [83]. 

In summary, the chemistry of the donor/acceptor-substituted carbenoids represents a new avenue of research for metal-catalyzed decomposition of diazo compounds. The resulting carbenoids are more chemoselective than the conventional carbenoids, which allows reactions to be achieved that were previously inaccessible. The discovery of pan-tolactone as an effective chiral auxiliary, and rhodium prolinates as exceptional chiral catalysts for this class of rhodium-carbenoid intermediate, broadens the synthetic utility of this chemistry. The successful development of the asymmetric intermolecular C-H activation process underscores the potential of this class of carbenoids for organic synthesis. 

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