TADDOL chiral auxiliaries

Seebach and coworkers have developed enantioselective conjugate additions of primary dialkylzinc reagents to 2-aryl- and 2-heteroaryl-nitroalkenes mediated by titanium-TADDO-Lates (Eq. 4.90). x a TADDOLs and their derivatives are excellent chiral auxiliaries.9611... 

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). 

The enantioselective addition of organomagnesium compounds to ketones can be most conveniently performed by using a chiral auxiliary in the substrate molecule. Primary aUsyhnagnesium reagents react with aryl and heteroaryl ketones in the presence of magnesium TADDOLate at — 100°C, yielding products with up to 98% ee (equation 143). Chiral a-ketoacetals 214, prepared in two steps from a-substituted cinnamic aldehydes, add organomagnesium species with up to 98% diastereoselectivity (equation 144). 

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). 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

Seebach, D., Beck, A. K. Heckel, A. (2001) TADDOLs, Their Derivatives, and TADDOL Analogues Versatile Chiral Auxiliaries, Angew. Chem., Int. Ed. 40, 92-138. 

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. 

The bis(dioxolanyl)oxazolidinone 33 has been prepared from D-mannitol and evaluated as a chiral auxiliary <02MT749> and the diamine 34 has been examined as a ligand for rhodium catalysed asymmetric hydrogenation of diethyl itaconate <02JOU104>. Deracemisation of 2-benzylcyclohexanone by formation of an inclusion complex with the TADDOL compound 35 has been described and the mechanism clarified by X-ray structure determination of the complex <02T3401>. A production process for the bis(phosphine oxide) 36 has been patented <02USP6472539>. 

The procedure described here is a typical one tor the preparation of a,a,a ,a -tetraaryl 2,2-disubstituted 1,3-dioxolane-4,5-dimethanols (TADDOLs, 1), a class of diols of which ca. 50 representatives have been synthesized.7 They have become useful chiral auxiliaries for the preparation of enantiomerically enriched or pure compounds and for analytical purposes. The diols themselves have been employed... 

D. Seebach, A. K. Beck, A. Heckel, TADDOL and Its Derivatives - Our Dream of Universal Chiral Auxiliaries , in Essays in Contemporary Chemistry From Molecular Structure towards Biology , Eds. G. Quinkert, M. V. Kisaktirek, Verlag Helvetica Chimica Acta, Zurich, 2001. 

TADDOL and Its Derivatives -Our Dream of Universal Chiral Auxiliaries )... 

The short preparative review presented here - without any consideration of mechanistic aspects - has hopefully demonstrated why we consider the TADDOL system a candidate for a universally applicable chiral auxiliary. It has all the features, first of all the synthetic availability and almost unhm-ited flexibility to be used not only for all types of enantioselective syntheses and resolutions (to prepare enantiomerically pure compounds, EPC [86] [87]),... 

There is another system, that of BINOL/BINAP, the Japanese dream of a universal chiral auxiliary [88], and there are striking similarities, but also fundamental differences, when compared with the TADDOLs (see Scheme 16). There is still a lot to do, and there are other competitors out there, sometimes referred to as preferred ligands (such as the semicorrine and oxazoline [89], the metallocene [90], the diaminocyclohexane [91], and the quinine/cincho-nine [92] systems). Everybody in the field of EPC synthesis dreams of hav-... 

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. 

Moreover, alkenylboronic esters can be modified by chiral auxiliaries, and especially the TADDOL auxiliary has been demonstrated to be an effective chiral inductor for the cyclopropanation reactions discussed here (Table In order to keep the... 

The widely used chiral auxiliaries, tetraaryl-l,3-dioxolane-4,5-dimethanols (TADDOLs), developed by Seebach and co-workers, have found applications in several fields of asymmetric synthesis (75). From their transition metal complexes, the titanium-containing ones (titanium-TADDOLates) are the most successful ones (see titanium complexes). 

Chiral titanium complexes with a, a, a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands are versatile auxiliaries in the Lewis acid catalyzed alcoholysis of racemic 4-(arylmethyl)-2-phenyl-5(477)-oxazolones 234, providing the corresponding enantiomerically enriched N-protected amino acid esters 235 (Scheme 7.73). The enantioselectivity of the reaction is dependent on the solvent, temperature, and chiral ligand. Selected examples of the alcoholysis of saturated 5(477)-oxazolones are shown in Table 7.21 (Fig. 7.23). 

Using these optimized conditions, the conjugate addition of 45 to the malonates 49 in the presence of the solid base provided access to the Michael adducts in good yields and high diastereoselectivities. The removal of the chiral TADDOL auxiliary could be accomplished without epimerization or racemization in this case, too. After esterification of the very polar acid intermediates with diazomethane the corresponding dimethyl esters 52 were obtained with yields of 72-94% and enantiomeric excesses ee of 84-94% (Scheme 1.1.13). 

The compounds form chiral metal complexes as well as chiral clathrates and can be used as auxiliaries (TADDOLs) for asymmetric syntheses [242]. 

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