Bidentate chiral auxiliaries

Bidentate chiral auxiliaries have since been examined. While camphane-2,3-diol and (5-binaphthol gave disappointing results, tartrate-derived (TADDOL) ligands were found to be very promising as chiral inductors [44]. Particularly interesting results were obtained by using complex 21, readily available from natural (P,J )-(+)-tartaric acid (Scheme 13.21). 

Lippard and co-workers [33] reported the same addition, but catalyzed by copperl(I) complexes with bidentate chiral auxiliary ligands (see Table 4, entry 2). The products, as precursors to prostaglandin synthesis, were formed in moderate yield and low e.e. when Cu(R-CHIRAMT), a chiral aminotropone imine, was used. However, higher enantiomeric excess purities (> 70%) were obtained when a silyl reagent and hexamethylphosphoramide (HMPA) were added. Not surprisingly, both catalysts gave similar products with similar enantiomeric purities. 

In catalytic enantioselective Diels-Alder reactions, Mg11 catalysts bearing chiral auxiliaries, such as chiral bidentate ligands containing oxazoline moieties,27-29 chiral diamines,30 and... 

Mg11 complexes are also effective for controlling asymmetric radical reactions.33,34 Moreover, enantioselective radical reactions using chiral Mg11 complexes have been studied, and high enantioselectivities have been realized in the presence of stoichiometric or catalytic amounts of chiral auxiliaries such as bis-oxazolines (Scheme 8).35-39 In most cases, substrates having bidentate chelating moieties are required. 

In most reported cases, the covalently bound chiral auxiliary has been attached to the dienophile via an acyl linkage, but there are also many examples known in which the auxiliary has been attached to the diene via an acyl, alkyl or heteroatom linkage, the first example of the latter being Trost s diene147. Lewis acids are often added to the reaction mixtures when the chiral auxiliary attached to the dienophile contains an additional Lewis basic site. This is not only to enhance the reaction rate, but especially to enhance the diastereofacial selectivity by complexing to the dienophile in a bidentate fashion. This makes the dienophile more conformationally rigid. 

Carbohydrates have found widespread use as chiral auxiliaries in asymmetric Diels-Al-der reactions156. A recent example is a study conducted by Ferreira and colleagues157 who used carbohydrate based chiral auxiliaries in the Lewis acid catalyzed Diels-Alder reactions of their acrylate esters 235 with cyclopentadiene (equation 66). Some representative results of their findings, including the ratios of products 236 and 237, have been summarized in Table 9. The formation of 236 as the main product when diethylaluminum chloride was used in dichloromethane (entry 3) was considered to be the result of an equilibrium between a bidentate and monodentate catalyst-dienophile complex. The bidentate complex would, upon attack by the diene, lead to 236, whereas the monodentate complex would afford 236 and 237 in approximately equal amounts. The reversal of selectivity on changing the solvent from dichloromethane to toluene (entry 2 vs 3) remained unexplained by the authors. 

Cadogan and coworkers160 developed a fructose-derived l,3-oxazin-2-one chiral auxiliary which they applied in the Diels-Alder reactions of its iV-enoyl derivatives 246 with cyclopentadiene using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded mixtures of endo 247 and exo 248 (equation 68). The catalyst binds to the chiral dienophile in a bidentate fashion (co-ordination to both carbonyl groups). As a consequence, the dienophile is constrained to a rigid conformation which accounts for the almost complete diastereofacial selectivities observed. 

This NOE idea was then extended to Pd(ii) allyl complexes with bidentate phosphine auxiliaries [99-111], with the ortho P-phenyl protons acting as the reporters (see 81). Figure 1.17 shows a section of the H, H NOESY for [Pd(P-pinene allyl) (Chiraphos)](OTf) (Chiraphos = Ph2PCH(CH3)CH(CH3)PPh2), 81 [129], and reveals the numerous contacts from the chiral phenyl array to the allyl ligand. 

Novel bidentate chiral Lewis acids derived from 1.8-naphthalenediylbis(dichloroborane) and modified amino acids as chiral auxiliary have been successfully utilized as effective catalysts for the asymmetric Diels-Alder reaction of a,[ -unsaturated aldehydes. The enantioselectivity is highly sensitive to the kind of chiral amino acids. Moderate enantioselectivity was obtained with the tryptophan-derived ligand for the endo adduct, but amino acids without aromatic groups... 

TADDOL is one of the oldest, and most extraordinarily versatile, chiral auxiliaries (Scheme 1.8). The initial design of TADDOL was driven by practical considerations, mainly because it is derived from tartaric acid - the least-expensive chiral starting material with twofold symmetry available from natural sources. The two hydroxyl functions of the genuine molecule can act as a double hydrogen-bond donor, allowing the formation of bidentate complexes. Moreover, these functions can be easily substituted, giving access to a variety of derivatives. 

Utility. Many asymmetric syntheses have been developed using vicinal diamines as the source of chirality. The major interest lies in their use as precursors for the synthesis of a broad family of bidentate ligands. Many reactions have also been described using the N-alkyl derivatives of these diamines as chiral auxiliaries and protecting groups of aldehydes. Most of these applications generally use the framework of l,2-diphenyl-l,2-diaminoethane (7) or 1,2-diaminocyclohexane (8), whose preparations have been fully described. ... 

Excellent yields and diastereoselectivities have been obtained in allylations using a new oxazolidinone chiral auxiliary derived from diphenylalaninol [24]. The use of oxazolidinone chiral auxiliaries was sparked by the application of Lewis acids to radical reactions. Bidentate Lewis acids are used to favor one rotamer (44) out of a possible four by forming a chelated intermediate with the two carbonyl groups and through steric interactions imparted by the 4-substituent of the oxazolidinone (Eq. (13.12)). Trapping with the allylstannane can then occur on the face opposite the bulky oxazolidinone-4-substituent. 

A similar allylation has been reported with the chiral auxiliary on the nitrogen of the bromoglycine attached as an imide rather than as an ester (Eq. (13.20)) [30]. A valinol-derived oxazolidinone chiral auxiliary 68 was employed under bidentate Lewis acid conditions (ZnCl2). It was found that ZnCla functions as a radical initiator as well as a Lewis acid in these reactions. The best example provides the allylglycine 69 derivative in 85% yield and the newly formed stereocenter in a ratio of 87 13 (R. S) with a reaction time of 1 h at -78 °C. 

Maruoka developed bidentate Lewis acids, with BINOL as chiral auxiliary, which... 

Within the past decade, diastereosolective radical reactions have become feasible and the factors contolling selectivity defined. Chiral auxiliaries for radical reactions have been recently developed in analogy to those developed for carban-ion chemistry in the 1970s and 1980s. The first example of stoichiometric use of a chiral ligand for enantioselective radical additions was recently reported by Porter and coworkers [59,60,61]. Reaction of the amide 14 with allyltrimethyl-silane at -78 °C, initiated by triethylborane, in the presence of 1 equiv. each of zinc triflate and the chiral bidentate ligand 15, provided the allylated product in a yield up to 88% and ee of 90%, Eq. (18). The presumed intermediate is the a-keto radical complexed to the chiral Lewis acid. 

Numerous research groups have shown that chiral auxiliaries can be used in free-radical reactions for the generation of new stereogenic centers [34], Sibi and Yamamoto have used oxazolidinone chiral auxiliaries in the presence of bidentate Lewis acid to create bicyclic intermediates and control the outcome of reactions (Scheme 11). 

Among the MgO samples screened in the asymmetric Michael addition of chalcone and dimethylmalonate using (1/ , 2/ )-( + )-l,2-diphenyl-l,2-ethylenediamine (DPED, see Figure 5.5) as a chiral auxiliary, NAP-MgO was found to be superior to NA-MgO and CM-MgO in terms of yields and ee s. In general, chiral bidentate systems eomposed of primary and secondary amines afforded better ee s, while chelation with -OH groups displayed no reaction and ee (Table 5.11). 

All four chiral auxiliaries are available derivatives of ephedrine. Structurally, they are vicinal amino-alcohols, which are able to act as l,4-N,0-bidentate ligands for many metal cations. The stability of such complexes generally enhances with the hardness of the central metal ion [17]. 

Silks and co vorkers reported anti-selective aldol reactions in conjunction vith their investigations on chiral selenium compounds [39]. They discovered that bidentate oxyaldehydes precomplexed vith TiCl4 led to anti aldol products in good yield and vith excellent stereoselectivity, as sho vn in Table 2.35, entries 1 and 2. Presumably, this chelation-controlled reversal of syn/anti selectivity is a phenomenon similar to that vhich Ghosh and co vorkers exploited to produce syn aldols from aminoindanol chiral auxiliaries. Both benzyl and isopropyl oxazolidineselone chiral auxiliaries have comparable anti diastereoselectivity. 

Matsuo J, Koga K. Enantioselective alpha-alkylation of phenylacetic acid using a chiral bidentate lithium amide as a chiral auxiliary. Chem. Pharm. Bull. 1997 45 2122-2124. 

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