Chiral auxiliary phenylethylamine

Further reactions of allyl organometallics with a-alkoxyaldimines 1, prepared from (S)-2-(methoxymcthoxy)propionaldehyde and (R)- and (S)-l-phenylethylamine, illuminate the difference in the influence of the nitrogen chiral auxiliary and the x-alkoxy center7. 

Reactions of nitro compounds with chiral imines have only recently been described. Either chiral 1-phenylethylamine (auxiliary) or the glyceraldehyde acetonide aldehyde was used as the chiral precursors of the imines 66 and 68, which reacted with 3-mesyloxynitropropane to give the 3-nitropyrrolidines dl)-67 and 69, respectively, with good diastereoselectivity. In fact, both products were obtained (almost) exclusively as trans diastereomers with high level of asymmetric induction, but the configurations of the newly formed stereocenters were not determined [44] (Scheme 13). N-Boc imines can be formed... 

In the presence of ZrCU or HC1, cyclization of y - a I k o x y a 11 y I s t a n n a n e 158 bearing (i )-(+)-l-phenylethylamine as a chiral auxiliary occurs to produce trans-fi-aminocyclic ether 159 with high de (91%). As shown in Scheme 3-55, asymmetric addition of an allyl group to the imine carbon can be explained by the modified Cram model 160. The attack of the allylic y-carbon approaches... 

It is important to mention again at this point that a general feature of the solid-state ionic chiral auxiliary approach to asymmetric synthesis is that not all chiral auxiliaries lead to high enantiomeric excesses. A case in point is found in the work of Natarajan et al. on the a-oxoamide-containing salts 43 (Scheme 10) [29]. Like the nonionic a-oxoamides discussed previously (Sect. 2.2), these compounds undergo photocyclization to p-lactam derivatives, and while the prolinamide salt behaves perfectly, leading to p-lactam 44 in 99% ee at 99% conversion, the corresponding 1-phenylethylamine salt affords nearly racemic photoproduct (3% ee at 99% conversion). The reason for this difference is... 

The formation of chiral, enantio-enriched imines by the utilization of optically active amines, and the subsequent hydrogenation of the diastereotopic imine faces provides a powerful method for the introduction of new stereogenic centers, often with high diastere-omeric excesses. New, optically active amines are then obtained by the removal of the chiral auxiliary group475. Thus, the condensation of 2-alkylcyclohexanones with optically active 1-phenylethylamine yielded the mixture of imines 42 and 43 which were hydrogenated over Raney Ni to give essentially only one optically active, diastereomerically... 

A final comment on Table 4 concerns the reaction shown in entry 8. Because the di-TT-methane photorearrangement of benzonorbomadiene derivatives requires triplet energy sensitization, we could not use typical, passive amines such as (/ )-( + )-l-phenylethylamine as chiral auxiliaries. We therefore prepared an optically pure amine to which a sensitizing benzophenone moiety was tethered, namely, the 4-benzoylphenyl ester of l-valine [25]. Photolysis of the salt of this amine at wavelengths where only the benzophenone chromophore absorbs led to the photoproduct in 91% ee at 100% conversion, a gratifying vindication of the concept. Optically active photosensitizers have been used in solution with limited success [33], but this represents the first example of simultaneous triplet-triplet energy transfer and asymmetric induction in the crystalline state. 

As can be seen from Tables 1-3, not all ionic chiral auxiliaries lead to high enantiomeric excesses. While we have always managed to find at least one chiral auxiliary that leads to good (and in many cases excellent) ee, there are at least an equal number that do not, and the researcher trying the method for the first time should be prepared to try half a dozen or more chiral auxiliaries in order to have a reasonable chance of finding a good one. As mentioned earlier, 1-phenylethylamine should be one of these, but on occasion even this usually reliable amine fails. 

The ionic chiral auxiliary approach was also applied to the enantioselective photocylization of tropolone. Irradiation of salt crystals of tropolone ether carboxylic acid 29 with several chiral amines afforded the enantiomerically enriched secondary products 31 [52]. The best results were obtained with optically pure 1-phenylethylamine and l-amino-2-indanol, which gave optical yields in the 60-80% ee range depending on the extent of conversion. 

Synthesis of Enantiomerically pure 2-Oxazolidinones and Tetrahydro-2//-l,3-oxazin-2-ones Using (5)-l-Phenylethylamine as Chiral Auxiliary... 

The iodocyclization of acyclic unsaturated isoureas containing (S )-phenylethylamine as the chiral auxiliary gave chiral cyclic isoureas, which are masked 1,2-diamines. Starting from (S)-phenyl-ethylamine, the corresponding cyanamide was easily obtained, which was then converted, after allylation, to the corresponding isourea. The iodocyclization of the isourea derived from (S)-phenylethylamine afforded an equimolar diastereomeric mixture of 4,5-dihydroimidazoles 4 in 90% yield, which were easily separated by chromatography167. 

If the chiral auxiliary used for the formation of diastereoisomers is covalently attached to the ferrocene derivative, other techniques such as chromatography may be applied for diastereoisomer separation. 1-Phenylethylamine is a comparatively... 

In addition to four component condensation, several other applications of chiral primary ferrocenylalkyl amines have been published. Thus, an asymmetric synthesis of alanine was developed (Fig. 4-3la), which forms an imine from 1-ferrocenylethyl amine and pyruvic acid, followed by catalytic reduction (Pd/C) to the amine. Cleavage of the auxiliary occurs readily by 2-mercaptoacetic acid, giving alanine in 61% ee and allowing for recycling of the chiral auxiliary from the sulfur derivative by the HgClj technique [165]. Enantioselective reduction of imines is not limited to pyruvic acid, but has recently also been applied to the imine with acetophenone, although the diastereoisomeric ferrocenylalkyl derivatives of phenylethylamine were obtained only in a ratio of about 2 1 (Fig. 4-31 b). The enantioselective addition of methyl lithium to the imine with benzaldehyde was of the same low selectivity [57]. Recycling of the chiral auxiliary was possible by treatment of the secondary amines with acetic acid/formaldehyde mixture that cleaved the phenylethylamine from the cation and substituted it for acetate. 

With a chiral auxiliary in (42) such as 1-phenylethylamine (R = CHMePh), the diastereomeric excess in the reaction is low (de < 30%) and only improves somewhat when TiCU catalysis is used to lower the temperature and simultaneous 1,4- and l,S-asymmetric induction is attempted. A more promising approach was found in the amino-Claisen rearrangement of IV-allylketene lV,(7-acetals (44), which are... 

The preparation of optically active cyclopropanecarboxamides 64 has been achieved starting from an organometallic chiral auxiliary. The (R)- and (5)-crotonoyliron complexes show good diastereoselectivity for the Z conformer when treated with diethylzinc, zinc(II) chloride and diiodomethane. A 10 1 mixture of (i ,i ,5// ,5,/ )-diastereomers was obtained. Starting from the (/i)-isomer, (-)-(/ )-62, decomplexation of the cyclopropanated intermediates (R,R,S)- and (R,S,R)-63 with bromine in the presence of (4-)-(7 )-l-phenylethylamine gave the corresponding cw-substituted amides 64 in a ratio of 10 1. 

The imine 19 derived from a phenylethylamine has been reported to react with various nucleophiles, such as organolithium reagents and cuprates, to generate the diastereoenriched amine following hydrogenolysis (H2/Pd) of the chiral auxiliary. However, the diastereoselectivities of these reactions are typically modest [36 38]. The seminal works of Takahashi [39] and later Pridgen [40] demonstrated that higher... 

Asymmetric induction occurs when (S)-l-phenylethylamine hydrochloride is used as the ammonium salt [57], which prompted Waldmann to investigate amino acid methyl esters as chiral auxiliaries the reaction of (S)-isoleucine methyl ester with cyclopentadiene in the presence of 35% aqueous formaldehyde solu-tion/tetrahydrofuran (9 1) afforded the best stereoisomeric ratio (93 7) [62],... 

Further investigations on the influence of the substituents on the terminal carbon of the olefin were reported by Ikeda and coworkers [26] employing the bromo enamides 96 as substrates. These studies revealed that two thiophenyl groups on the terminal olefinic carbon accelerate the 4-exo trig cyclization to synthetically useful levels. Subsequently, these reactions were applied in the total syntheses of the P-lactam antibiotics PS-5 and thienamycins first in racemic form and later in optically active forms, employing (x-phenylethylamine as the chiral auxiliary. 

Scheffer et al. (Chapter 1) have shown how the use of ionic chiral auxiliaries as a means of immobilizing ketoacids (5) within crystals results in excellent yields of cyclized products upon irradiation, and with high ee. With (5)-(+)-1-phenylethylamine as the salt-forming amine, for example, a quantitative yield of (6) with 98% ee was obtained. The corresponding i amine similarly gave a quantitative yield of the enantiomer of (6) with an ee of 97%, and other chiral amines were also tried with success. 

---