Chiral auxiliaries transesterification

Removal of the f-butyloxycarbonyl groups was obtained by treatment of 34a with a solution of trifluoroacetic acid in dichloromethane (1 1,0°C, 3 h). N-N-Hydroge-nolysis was achieved under H2 (75 psi, rt, 15 h) in the presence of a catalytic amount of Pt02 in ethanol to afford crystalline a-amino esters 36. Finally, the chiral auxiliary was cleaved and regenerated by nondestructive transesterification in the presence of Ti(OEt)4. The a-amino acid hydrochlorides (5)-37 were obtained by heating the crude amino acid ethyl esters in 6 N aqueous HC1 and after evaporation of the solution (Scheme 16). 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

In reactions with acyclic dienes, the stereoselection with the (S)-valinol-derived cro-tonate imides is only about 3 1, but diastereoselection is high with N-acyl oxazolidines derived from phenylalanine. The chiral auxiliary is cleaved by transesterification with lithium benzyloxide in 85-95% yield. ... 

Removal of the chiral auxiliary is easily achieved by hydrolysis with lithium hydroxide or transesterification with titanium tetrabenzyloxide [Ti(OBn)J affording the carboxylic acids 8 (esters 9) and recovered oxazolidinone 10. 

DCP as a Chiral Controller in Oxidative Free Radical Cyclizations. As a chiral auxiliary, DCP (1) is also reported to induce modest diastereoselection (60% de) in Mn(III)-based oxidative free-radical cyclizations of p-keto esters (eq 12). Chiral p-keto ester 25 was prepared by transesterification reaction with methyl ester 23, 1, and 0.3 equiv of DMAP (catalyst) in anhydrous toluene at reflux for 3-5 d as described by Taber. Oxidative cyclization of a 0.1 M solution of 24 in AcOH with 2 equiv of Mn(OAc)3-2HzO and 1 equiv of Cu(OAc)3 HzO provided bicyclo[3.2.1]octan-2-one (25). 

The following transformations demonstrate the characteristie feature of titanium alk-oxide-catalyzed transesterification. The isolated double bond does not enter into conjugation with the active methylene moiety (Eq. 218) [515]. Removal of a sterically demanding chiral auxiliary was possible without affecting the ketoester moiety (Eq. 219) [516,517]. Preparation of an allyl ester was achieved in good yield with retention of the nitrone moiety essential for subsequent cycloaddition (Eq. 220) [518]. 

The second step is a transesterification reaction and recovers the valuable chiral auxiliary used in the preceding step. 

We have introduced you to this chiral auxiliary before any other because it is more commonly used than any other. It is a member of the oxazolidinone (the name of the heterocyclic ring) family of auxiliaries developed by David Evans at Harvard University, and is easily and cheaply made from the amino acid (S)-valine. Not only is it cheaply made it can also be recycled. The last step of the route above, transesterification with benzyl alcohol, regenerates the auxiliary ready for re-use. synthesis of Evans s oxazolidinone chiral auxiliary from (S)-valine NH2 NH2... 

The first approach to this problem was to attach the chiral auxiliary to the diene by a vinylogous trans-esterification reaction of chiral alcohols with the 3-alkoxy enones (Scheme 21). This reaction was used to construct a variety of chiral dienes including the menthol and phenmenthol dienes (55a) and (55b) by transesterification followed by enol silylation using the Simchen procedure (RsSiOTf taN). However, these dienes exhibit poor diastereofacial selectivity despite the precedent for high stereochemical control in homo Diels-Alder reactions by the use of similar auxiliaries on a,P-unsaturated enones. ... 

In 1982, Evans reported that the alkylation of oxazolidinone imides appeared to be superior to either oxazolines or prolinol amides from a practical standpoint, since they are significantly easier to cleave [83]. As shown in Scheme 3.17, enolate formation is at least 99% stereoselective for the Z(0)-enolate, which is chelated to the oxazolidinone carbonyl oxygen as shown. From this intermediate, approach of the electrophile is favored from the Si face to give the monoalkylated acyl oxazolidinone as shown. Table 3.6 lists several examples of this process. As can be seen from the last entry in the table, alkylation with unactivated alkyl halides is less efficient, and this low nucleophilicity is the primary weakness of this method. Following alkylation, the chiral auxiliary may be removed by lithium hydroxide or hydroperoxide hydrolysis [84], lithium benzyloxide transesterification, or LAH reduction [85]. Evans has used this methology in several total syntheses. One of the earliest was the Prelog-Djerassi lactone [86] and one of the more recent is ionomycin [87] (Figure 3.8). 

Atorvastatin, 217, a HMG-CoA inhibitor developed by Pfizer is a popular treatment for hypercholesterolemia. An early as)mimetric synthesis of the drug used an aldol reaction between the magnesium enolate of Braun s reagent 214 and aldehyde 213 to afford alcohol 215 in 97% ee and 60% yield (Scheme 14.75). Subsequent transesterification was used to remove the chiral auxiliary affording compound 216. 

A highly diastereoselective Paterno-Buchi reaction by a new approach was reported by Bach et The chiral auxiliary bound to m-hydroxybenzaldehyde 5 offers a binding site to which the reaction partner can be attached by two hydrogen bonds. In the complex, the two enantiotopic faces of the alkene 6 become diastereotopic and can be differentiated. The dihydropyridone 6 approaches the aldehyde from one face only (Scheme 4). Because the reaction within the complex is presumably faster than the reaction with unbound dihydropyridone, the face selection is enhanced by this rate acceleration. In toluene at -10 C, lactam 5 was converted with high diastereoselectivity to diastereoisomer 7 (>90% DE). The oxetano[2,3-fo]piperidone fragment could be cleaved from the auxiliary by transesterification (NaOMe in MeOH). 

Scheme 1.4. Selective synthesis of (k)- and (fC)-bis[di(ethoxycarbonyl)methano][60]fuIlerene by diastereoselective tether-directed bis-cyclopropanation of Cgo and subsequent transesterification under removal of the chiral tether auxiliary.

An alternative to 138 and 122 is (R)- or (5)-2-hydroxy-l,2,2-triphenylethyl acetate ((/ )-or (5)-HYTRA) (14.3). a chiral acetate which does not need an auxiliary heteroatomic substituent. Compound 143 is readily available through acylation of 1,2,2-triphenyl-1,2-ethandiol with acetyl chloride or acetic anhydride. Its dianion, generated by double deprotonation with LDA and transmetallation with MgBr2 or Mgl2, reacts with aliphatic and aromatic aldehydes to give )8-hydroxy acid derivatives with diastereomeric ratios ranging from 92 8 to 98 2 . The crude adducts can be readily purified by crystallization. Removal of the auxiliary can be accomplished either hydrolytically (KOH, aq. MeOH) or transesterification (MeONa, MeOH/THF) to provide the respective j8-hydroxy acid/ester in enantiomerically pure form. 

One of the key pioneers in this area was Solladie, who thoroughly investigated the reactions of chiral sulfoxide carbanions [21], Their diastereoselec-tive additions to ketones and aldehydes are illustrative of the method (Scheme 13.16) [67]. Addition of 104 to cyclohexyl methyl ketone (105) thus furnished adduct 106. The sulfoxide, having fulfilled its role as an auxiliary, is subsequently subjected to reductive cleavage to afford hydroxy ester 107. After transesterification, alcohol 108 was produced in 95 % ee. Despite the numerous years that have transpired since these results were first published, such optically active tertiary alcohols remain otherwise difficult to prepare, a feature that attests to the potential value of chiral sulfoxide anions in asymmetric synthesis. 

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