TADDOL esters

The so-called TADDOLs of general structure 235 have found many applications and, as a result, the synthesis of new derivatives has been of interest. Derivatives synthesized include 40-44 <1997BSF315>, mono- and di-unsatu-rated TADDOL esters <2005S2491>, TADDOL-crown ether hybrids <2001S647>, and unsymmetrical derivatives 254 <2001CCL489>. A new Weinreb amide-based route to compounds 255 has appeared <2006S2159>. 

There have again been a number of important developments involving derivatives of TADDOLs 44. A range of new mono- and di-unsaturated TADDOL esters have been prepared <05S2491> and dimeric TADDOLs have been produced and used for molecular recognition of... 

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). 

Narasaka et al. demonstrated the utility of titanium-ligand complexes in the resolution of chiral a-aryl esters [52]. Ti(Oi-Pr)4-ligand 56 complex resolves 2-pyridine thioesters with high selectivities (fcrei=26-42, see Scheme 13). Seebach and co-workers have examined titanium-TADDOLate complexes as reagents for the ring opening of meso anhydrides, dioxolanones, and azalactones [53]. Addition of an achiral isopropoxide source renders the desymmetrization of meso... 

Whilst the use of Taddol as an asymmetric phase-transfer catalyst for asymmetric Michael reactions was only moderately successful, it was much more enantioselec-tive in catalyzing alkylation reactions. For this study, Belokon and Kagan employed alanine derivatives lib and 16a-c as substrates, and investigated their alkylation with benzyl bromide under solid-liquid phase-transfer conditions in the presence of 10 mol % of Taddol to form a-methyl phenylalanine, as shown in Scheme 8.8. The best results were obtained using the isopropyl ester of N-benzylidene alanine 16b as substrate and sodium hydroxide as the base. Under these conditions, (R)-a-methyl phenylalanine 17 could be obtained in 81% yield and with 82% ee [19]. Under the same reaction conditions, substrate 16b reacted with allyl bromide to give (R)-Dimethyl allylglycine in 89% yield and with 69% ee, and with (l-naphthyl)methyl chloride to give (R)-a-methyl (l-naphthyl)alanine in 86% yield and with 71% ee [20]. 

Lopp and co-workers modified the Sharpless-Katsuki Ti-complex [Ti(0-iPr)4, t-BuOOH and ester of tartaric acid ligand] by changing the tartaric acid ester by another chiral ligand such as TADDOL (a,a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol, 7.29). 

Introduction. Ti-TADDOLates are a,a,a, a -tetraaryl-2,2-disubstituted l,3-dioxolane-4,5-dimethanolatotitanium derivatives. The most common substituents are R, R = Me/Me and Ph/Me, Ar=Ph and 2-naphthyl, X, Y = C1/C1, t-PrO/Cl, Cp/Cl, and i-PrO/i-PtO. The corresponding TADDOLs (2) are available in both enantiomeric forms from tartrate esters which are acetalized (R R CO) and allowed to react with aryl Grignard reagents. The reactions performed in the presence of Ti-TADDOLates or with Ti-TADDOLate derivatives include nucleophilic additions to aldehydes - - and nitroalkenes of alkyl, aryl, and allylic - groups aldol additions hydrophosphonylations and cyanohydrin reactions of aldehydes inter- and intramolecular Diels-Alder additions ... 

Other Enantioselective Transformations Mediated by Ti-TADDOLates. The iodolactonization of 2-allyl-2-hydroxy-4-pentenoic acid shown in eq 8 gives (21) in a 67% yield (after cyclization of some iodo isopropyl ester formed as a side product), the iodolactone is a single (—)-diastereoisomer with a 5 1 (S,S)I(R,R) ratio. The TADDOLate generated in situ was employed in stoichiometric amount. The two enantiomers of 2-pyridyl 2-phenylthiobutyrate react with a rate difference of 39 1 with excess isopropanol in the presence of 0.1 equiv of a Ti-TADDOLate under the conditions specified in eq 9. This leads to the isopropyl ester (22) containing 96% of the (/ )-enantiomer... 

The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,y3-unsaturated carbonyl derivatives, the Mukaiyaraa Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [108], Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (/-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectiv-ity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from 5-diphenylmethyl ethanethioate proceeds highly enantioselectively. Sco-lastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectiv-ity (Sch. 44) [110]. 

Nitrone cycloaddition reactions promoted by dichlorotitanium TADDOLate can be improved by using A(-(2-alkenyl)succinimides as the dipolarophiles. Regioselective and enantioselective formation of cyclopentenecarboxylic esters is observed using 8 to catalyze the [3+2]cycloaddition of 2,3-butadienoates with electron-deficient alkenes. ... 

One of the most important specific applications of tartaric acid is the preparation of Seebach s TADDOLs, e.g. 40. The dimethyl ester 38 is protected as the acetal 39 and reacted with four molecules of an aryl Grignard to give the TADDOL13 40. All these compounds are C2 symmetric and various TADDOLs have found applications as resolving agents, NMR additives, asymmetric catalysts and so on.14 Some of these will feature later in the book. 

Reductive aldol reaction of l-alken-3-ones and cinnamic esters depends on generating Rh enolates and the presence of chiral ligands turns such a process enantioselective. Effective ligands of very different structural types have been identified, and they include TADDOL phosphine 71 and BOX ligand 72. ... 

Reviews. Seebach el al. provide a general review of these reagents, for which he has coined the abbreviation TADDOL. At the present time there are 26 known reagents of type 1 (C2-symmctrical) and 12 of type 2 (C -symmetrical). In addition there arc analogous compounds with heteroaryl, alkenyl, and alkyl substituents in place of the aryl group of 1 and 2. All arc prepared by reaction of (R,R)-tartratc ester acetals with aryl... 

The conversion of meso-anhydrides to chiral monoisopropyl esters can be performed by reacting with diisopropoxytitanium TADDOLates. ... 

Note that the diastereoselective synthesis of cis-l,2-dialkyicyclopropanol is considerably improved by using (i-PrOljTiCl or (i-PrO) Ti with RCHjCH MgBr (where R > H). The procedure is further simplified by adding an alkyl bromide to a mixture of the ester, (i-PrOljTiCl, and Mg in THF at room temperature, thus obviating the preparation of the Grignard reagent. In the presence of a chiral TADDOLate, the reaction becomes enantioselective. 

Scheme 7. Examples for Enantiomer Separations by Crystallization with TADDOLs. Besides the original TADDOL (from tartrate acetonide and PhMgX), Toda et al. [44] have often used the cyclopentanone- and cyclohexanone-derived analogs. The dynamic resolution (resolution with in-situ recychng) of 2-(2-methoxyethyl)cyclohexanone was reported by Tsunoda et al. The resolved compounds shown here are only a small selection from a large number of successful resolutions, which include alcohols, ethers, oxiranes, ketones, esters, lactones, anhydrides, imides, amines, aziridines, cyanohydrins, and sulfoxides. The yields given refer to the amount of guest compound isolated in the procedure given. Since we are not dealing with reactions (for which we use % es to indicate enantioselectivity with which the major enantiomer is formed), we use % ep (enantiomeric purity of the enantiomer isolated from the inclusion...

Maruoka and co workers have obtained high ees in the alkylation of imine (12.45) using the C2-symmetric ammonium salt (12.51), and have applied this catalyst to the alkylation of the corresponding amide, Weinreb amide and also cyclic P-keto esters. Phase transfer reactions are not limited to quaternary ammonium salts for a successful outcome. Even the diol TADDOL (see Section 8.1) has been shown to be effective in the alkylation of related imines. ... 

The enantioselective a-chlorination of -keto esters was achieved with up to 88% ee using NCS with a commercially available TADDOL ligand. The chiral bisoxazoline copper(II) complexes have also been reported to induce the asymmetric a-chlorination of -keto esters when reacted with NCS. The asymmetric a-chlorination of aldehydes has been achieved using NCS and (2/ ,5/ )-diphenylpyrrolidine as a chiral catalyst. For example, the enantioselective chlorination of 3-methylbutanal with NCS proceeds in 95% yield and 94% ee (eq 17). ... 

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 first successful approach to a directly enantioselective variant of the method was achieved with Seebach s (r Pr)2Ti-TADDOLate, which served both as a chiral Lewis acid and as the O-nucleophile (Scheme 5.8). This titanium complex reacted with a biaryl lactone, yielding the corresponding ester with a moderate selectivity. ... 

A longer distance between both hydroxy groups is realized in the so-called TADDOLs (a,a,a, a -tetraaryl-l,3-dioxolan-4,5-dimethanol) [48]. These alcohols, widely employed in catalysis by Seebach, are accessible from tartrates by prior acetalization of the diol unit and subsequent reaction of the ester groups with 4equiv of aryl-Grignard reagents, as shown exemplarily with PhMgBr (Scheme 2.77) [49]. 

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