Other Chiral Auxiliaries

Ahn and coworkers developed stilbenediamine-derived 1,2,5-thiadiazoli-dine-1,1-dioxide-based chiral auxiliary 140 and demonstrated its utility in syn aldol reactions [49]. Excellent selectivity and yield were observed for a variety of aldehydes, as shown in Table 2.24, entries 1-3. The cyclic sulfa-mide auxiliary is novel in that it is bifunctional and C2-symmetric, so only 

Other chiral auxiliaries used in syn aldol reactions. 

Hitchcock and covrorkers developed ephedrine-derived 3,4,5,6-tetrahydro-21-f-l,3,4-oxadiazin-2-one-based chiral auxiliary 141 and demonstrated its utility in aldol reactions [50]. It vas discovered that the aldehyde had to be present during enolization for reaction to occur, because of difficulties in enolization. Use of aromatic aldehydes resulted in good yield and good to excellent selectivity, as did aliphatic aldehydes vithout a-hydrogen atoms. This method is not useful for aldehydes bearing a-hydrogen atoms, because of self-condensation. 

3 Synthesis of Optically Active syn Aldols Using Chiral Titanium Ligands 

Duthaler and co vorkers used carbohydrate-titanium complexes for synthesis of optically active syn-/i-hydroxy-a-amino acids [51]. These syn-a-aminoaldols vere obtained in moderate yield and excellent syn diaster-eoselectivity, as shosvn in Table 2.25. Transmetalation of the lithium enolate of glycine ester derivative 145 svith chiral titanium complex 146 provided a titanium enolate svhich upon reaction svith a svide variety of aldehydes provided syn-j5-hydroxy-a-amino esters 148. Subsequent hydrolysis and N-protection gave a-aminoaldols 149. 

An epimer of ( )-menthol, neomenthol, has been sporadically used. For example, King and co-workers managed to obtain an optically pure 

The derivatives 101 were prepared as a crystalline 1 1 epimeric mixture from which the Rp diastereomer could be isolated in 32% yield and 95% de. Alkaline hydrolysis at room temperature provided (5)-100 in 75% yield without any loss of optical purity. Unfortunately, (S pl-lOl could not be obtained in high diastereoselectivity. The same route with menthol failed due to the lack of crystallinity of the menthyl esters. An important characteristic of this method is that rac-100 was obtained by boronation and monomethylation of tcrt-butyl-phosphine. This is one of the very few occasions where a primary alkyl 

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The addition of lithium dimethyl-, dibutyl-, diphenyl- or 1-butenylcuprate to 2d produced (JiS) 94% ee, ifiS) 95% ee, (jiR) 96% ec, and ifiR) 90% ee, respectively. In this case the difference between S and R results from the CIP selection rules and not to the steric course of the reactions. The conformation of the chiral auxiliary in 1 d is such that one IV-methyl group is axially, the other equatorially, arranged on the bicyclic structure. The reagents attack the double bond from the side opposite to the equatorial iV-methyl group. Other chiral auxiliaries such as a-c14 were less effective15. 

Asymmetric autocatalysis using (5)-pyrimidyl alkanol 2a with only 2% ee afforded (5)-2a with an increased ee of 10%, [Eq. (9.4)]. The (5)-2a obtained with 10% ee was then used as an asymmetric autocatalyst for the following asymmetric autocatalysis. (5)-Pyrimidyl alkanol 2a with an increased ee of 57% was obtained. The subsequent consecutive asymmetric autocatalysis and the use of that product as an asymmetric autocatalyst for the following round gave (5)-pyrimidyl alkanol 2a with 81 % and 88% ee, respectively. Thus, the overall process was the asymmetric autocatalysis of (5)-2a starting from a low ee of 2% with significant amplification of chirality to 88% ee, with the increase in the amount without need for other chiral auxiliary. ° This stands as the first example of an asymmetric autocatalysis with amplification of ee. In addition, one-pot asymmetric autocatalysis of pyrimidyl alkanol 2b also significantly increased the chirality from 0.28 to 87% ee. ... 

Acrylates with other chiral auxiliaries such as 2-bomyl (181,182), or 2- or 3-menthyl (183) groups afforded the isoxazoline diastereomers with poor-to-good diastereoselectivity. Rotamers about the C O bonds were not considered in these cases. 

When using the corresponding cinnamyl compound, regioselectivity depends on the size of the alkyl halide. The a-product predominates with iodomethane (90% yield, d.r. >96 4, S) or iodoethane (79% yield, d.r. >96 4, 5), whereas 2-iodopropane attacks the y-position preferably (85% yield, d.r. 89 11, R)5- 52 53. Introduction of other chiral auxiliaries gave no improvement53. 

Instead of alanine and valine, several other chiral auxiliaries have been used, such as tert-leucine13, leucine14 and isoleucine15. In some cases diastereomeric excesses may be higher with the dihydropyrazines 5 and 6, derived from 0,0-dimethyl-alkylation with 3-bromo-propyne gives a de of 60% with (2S)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine (3), in contrast to 85% de with 516 and >95% de with 613. 

Other chiral auxiliaries like Oppolzer s bornanesultam 35 or chiral oxazolidinone 36 gave excellent results in stereocontrol and yield (Figure... 

Other chiral auxiliaries for the cyclopropanation of a,/ -unsaturated aldehydes have also been developed (Figure 7, 16-18) . a,/3-Unsaturated chiral amides have also been used in auxiliary-based reactions but the addition of diethyl tartrate as chiral additives was necessary for high diastereoselectivities ". 

Other chiral auxiliaries have been tested, such as those derived from TADDOL ligands, but, in these cases, better diastereocontrol was achieved using palladium acetate/diazomethane or using double differentiation with a chiral catalyst vide infra). 

Other chiral auxiliaries have been used besides menthol. Sulfoxide Designations ... 

Moreover, when these alkanols with low ee are utilized as asymmetric autocatalysts, 5-pyrimidyl alkanol 28 [48], 3-quinolyl alkanol [49],and 5-carbamoyl-3-pyridyl alkanols [50] with higher ees were obtained. The successive reactions were performed in order to make the best use of the autocatalysis, that is, the products of one round served as the asymmetric autocatalysts for the next. In the case of pyrimidyl alkanol, staring from (S)-alkanol 28a with only 2% ee, the ee reached almost 90% after four rounds [48] without the assistance of any other chiral auxiliary (Scheme 14). 2-Alkynyl-5-pyrimidyl alkanol 28b [5] and 2-... 

Virtually identical results, except in the opposite stereocontrol sense, are obtained with the use of Rh2(5S-MEPY)4. With d-menthyl diazoacetate and the same series of alkynes, selecti vibes as high as >97 3 diastereomer ratio have been achieved (Table 5.10), but diastereoselectivi-ties with diazoacetates having other chiral auxiliaries did not show any improvement in diastereocontrol [109]. 

Other chiral auxiliaries have been employed in this strategy for the synthesis of optically active alcohols.62... 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

This chapter focuses on the importance of cis-1 -amino-2-indanol as a chiral template in the development of new methodologies for the asymmetric synthesis of organic compounds. Other chiral auxiliaries are discussed in Chapter 23. The use of the amino alcohol 1 in resolutions is discussed in Chapter 8, whereas applications of 1 as a ligand are in Chapter 17. 

Although carbohydrates are cheap and readily available chiral compounds, their application in stereoselective synthesis was for a long time limited to ex-chiral-pool syntheses [3]. They have been considered too complex compared to other chiral auxiliaries, for example a-pinene in borane-chemistry [4] or BINAP-derivatives in reduction chemistry [5]. However, it has been shown during the past few years that carbohydrates can be successfully applied as stereodifferentiating tools in many different reaction types such as aldol- [6], hydrogenation- [7], carbonyl addition- [8], Michael- [9], Diels-Alder- [10], hetero-Diels-Alder [11], and rearrangement reactions [12]. 

With these points in mind, we summarize in Table 4 all of the published examples of the use of the solid-state ionic chiral auxiliary method of which we are aware, including, for comparison purposes, the three reactions discussed above (entries 17-19). In order to conserve space, results are reported only for the chiral auxiliaries that gave the best results. The interested reader may wish to consult the original papers for a more detailed account of the work and to see what other chiral auxiliaries were tried. 

A precursor to the pharmaceutical Paroxetine was obtained in good yield and 96% ee. Addition of phenyl Grignard to a chiral a, P-unsaturated enoylsultam followed by epimerization to the thermodynamically more stable C-3, C-4 trans isomer provides the desired compound <03TL5355>. Other chiral auxiliaries gave lesser or negligible ee. 

Michael additions with 8-phenylmenthyl esters of unsaturated acids Chiral auxiliaries attached elsewhere in asymmetric Michael additions Other Chiral Auxiliaries in Conjugate Addition The Evans oxazolidinones Chiral sulfoxides Asymmetric Birch Reduction Birch reduction of benzene Asymmetric Birch reduction of heterocycles... 

A number of other chiral auxiliaries have been tested. Although the methods illustrated below are quite effective, in practical terms it seems unlikely that they will be favored over some of the enantioselective catalytic methods discussed elsewhere in this volume. 

Continuing on this tack, Grundon and co-workers4 were able to obtain optical purities in the range of 14-22% ee. They achieved this improvement by employing 1 1 complexes of leucine methyl ester and diborane 4 in THF. Furthermore, their results were facilitated by the addition of one equivalent of BF3-etherate. Other chiral auxiliaries used include Z-valine methyl ester and p-phenylalanine methyl ester. 

We discuss other chiral auxiliaries and other strategies for controlling facial selectivity in Section 2.1.3 of Part B. 

One of the governing principles in the TADDOL system is the conformational lock and steric bias provided by the geminal diarylmethyl group. The question arises whether there are other chiral auxiliaries exploiting this gem-iml-diaryl effect. Indeed there are some are shown in Scheme 17. We expect to see more examples for the preparation and use of diarylmethanol derivatives in EPC synthesis and other chirality-creating processes. 

Highly selective Diels-Alder reactions with other chiral auxiliaries attached to the dienophile have been documented. For example, chiral 2-oxazolidinones or the camphor sultam auxiliaries have proven particularly useful. Such cycloaddition reactions, catalysed by an alkylaluminium chloride, occur with a variety of dienes to give adducts in high yield and with very high diastereoselectivity. In many cases these adducts can be obtained diastereomerically pure by crystallization. The reactions are thought to occur by way of complexed ion pairs (e.g. 129), in which the substituent on the auxiliary shields one face of the dienophile from attack by the diene. For example, 2-methylbutadiene (isoprene) gave the adduct 127, which was converted into (i )-(+)-a-terpineol 128 (3.92). ... 

This means that an absolute asymmetric synthesis from optically inactive prochiral molecules, free of chiral contaminations and run under chiral conditions can be realized, even without the action of circular polarized light or other chiral auxiliaries. 

Other chiral auxiliaries have been used besides menthol. 

One should note that several other chiral auxiliaries were appended to the P-ketoester starting material and some did lead to modest diastereoselectivity (-1.5 1). However, none of these products crystalUzed as readily, leaving the initially developed chemistry with 37 as the most practical route to 40. 

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