Benzyl ester, enantioselective

Asymmetric alcoholyses catalyzed by lipases have been employed for the resolution of lactones with high enantioselectivity. The racemic P-lactone (oxetan-2-one) illustrated in Figure 6.21 was resolved by a lipase-catalyzed alcoholysis to give the corresponding (2S,3 S)-hydroxy benzyl ester and the remaining (3R,4R)-lactone [68]. Tropic acid lactone was resolved by a similar procedure [69]. These reactions are promoted by releasing the strain in the four-membered ring. 

In a related approach, Padovani et al. prepared copolymers of styrene and a styrene derivative containing two pendant ester bonds using free-radical polymerization (Scheme 15) [108], Transesterification reactions were conducted with Novozym 435 as the catalyst and benzyl alcohol or (rac)-l-phenylethanol as the nucleophile. Interestingly, the ester bond closest to the polymer backbone (position A in Scheme 15) remained unaffected, whereas ester bond B reacted in up to 98% to the corresponding benzyl ester. The transesterification was not only highly chemoselective but also enantioselective. Conversion of (rac)-l-phenylethanol in the transesterification reaction amounted to a maximum conversion of 47.9% of the (/ )-alcohol, and only at the ester position B. 

A biphenyl and ct-methylnaphthylamine-derived chiral quaternary ammonium salt 23d, which was shown by Lygo to be effective for the asymmetric alkylation of Schiffs base 20, was also effective in the Michael reaction (Scheme 7.12) [43]. Notably, the enantioselectivity was highly dependent on the reaction conditions and substrates used. The Michael reaction of imine esters such as benzhydryl and benzyl esters with a,p-unsaturated ketones under solid-liquid phase-transfer catalysis conditions afforded the Michael adduct in up to 94% ee and 91% ee, respectively, while the tert-butyl ester showed moderate enantioselectivity (Scheme 7.12). Interestingly, in contrast to earlier reports, acrylate [42] and acrylamides failed to undergo the Michael reaction under these optimized conditions. 

The synthetic applicability is somewhat limited in that the asymmetric induction is very substrate dependent. Esters other than benzyl esters showed lower enantiomeric excesses. The substitution pattern at the 7 position has a drastic effect on the efficiency of the asymmetric induction. Monosubstitution led to enantioselectivities around 35% ee (with inductor 19, — 40°C). In the case of unsubstituted 7 position, the induction went down to 10% ee [39]. For lactones, enantioselectivities up to 43% ee were reported (inductor 20, — 55°C) [40]. 

Palladium-catalyzed carboalkoxylation of imidoyl iodides 6 provides benzyl [9] and even te/t-butyl[10] esters 7. Asymmetric hydrogenation of the imino moiety of imono esters 7 in a Pd(OCOCF3)2 / (7 )-BINAP / CF3CH2OH system gives enantio-enriched amino esters 8 in 85-91% ee (see Scheme 9.2) [11].The enantioselectivity achieved by the hydrogenation was much better than that by Corey s hydride reduction [12] and was employed for the syntheses of enantiomerically pure A-Boc-(3,(3-difluoroproline benzyl ester 9 (see Scheme 9.3)[13] and enantiomerically enriched A-Boc-P -difluoroglutamic acid benzyl ester [13]. 

Next to Muzart s work, Baiker and coworkers reinvestigated the reaction parameters of the palladium-catalyzed EDP of cyclic [i-kcto esters in the presence of various chiral proton sources including cinchona alkaloids [31]. When working with benzyl ester 55a as model compounds, they demonstrated the crucial effect of the solvent on the enantioselectivity of the reaction. In the palladium-catalyzed debenzylation of 55a carried out at room temperature with hydrogen, the highest conversions but the lowest enantioselectivities were achieved in protic polar solvents... 

This zinc-promoted reaction has been used with a variety of carbonyl compounds. Thus, the Luche conditions were applied in a synthesis of (-1-)-muscarine using an aldehyde derived from ethyl lactate [109]. Allyl halide condensation onto a-ketoamides of proline benzyl ester gave good diastereoselec-tivity when performed in the presence of zinc dust and pyridinium p-toluene-sulfonate in a water/THF mixture. In this way, a-hydroxy ketones were obtained with good enantioselectivity after removal of the chiral auxiliary [110]. Reactions of allyl bromide under the Luche conditions with y-aldo esters afforded y-hydroxy esters, which were converted in a one-pot reaction to y-allyl-y-butyro-lactones (Scheme 22) [111]. 

Some simple esters of proline have found applications as auxiliaries. Thus, the methyl ester 2 was used to form chiral amides for hydride reductions (Section D.2.3.3.). Methyl and benzyl esters 2 and 3 form amides with various types of carboxylic acids which are used in the addition of zinc or titanium species to carbonyl groups (Section D. 1.3.3.3 ). The amide of (S)-proline [(S)-4] has been used in enantioselective Michael additions (Section D.I.5.8.), and (5 )-Ar-tri-fluoroacetylproline [(.S)-5] is the only simple A-acyl derivative used as an auxiliary (Section D.l.1.2.2,). 

Proline benzyl ester 3 is the starting material for a variety of A -substituted derivatives formed by A-acylation with unsaturated acids, which are useful chiral dienophiles for enantioselective Diels-Alder reactions (Section D. 1.6.1.1.1.). The synthesis of these derivatives, e.g., (S)-6 or (S)-7 is conveniently achieved by A-acylation of the hydrochloride or tosylate of the benzyl ester (the allyl ester may also be used) of proline with triethylamine/4-(dimethyl-amino)pyridine5. 

The dibenzyl ester 27 can be obtained by slowly distilling a mixture of tartaric acid and benzyl alcohol, without adding an acidic catalyst34. It is a key intermediate in the synthesis of mono-O-acylated tartaric acids 28-31 33,35 the benzyl ester groups can be selectively cleaved to the free carboxylic acid groups by catalytic hydrogenation. Such derivatives form acyloxy-boranes with diborane which are used as chiral catalysts in enantioselective Diels-Alder reactions (Section D. 1.6.1.1.1.). 

One approach to ent-4 -tetrahydrocannabinol, which is independent ofthe chiral pool, was developed by David Evans (reaction scheme see next page). [143] Via enantioselective Diels-Alder reaction on a copper-bis-(oxazoline) complex, there is obtained a cyclohexenecarboxamide, which after conversion into its benzyl ester and an exhaustive Grignard reaction gives ent-menth-l-ene-3,8-diol. Also this isomer can be converted in an analogous matmer stepwise into tetrahydrocannabinol. A -Tetrahydrocannabinol would be correspondingly accessible by use ofthe antipode ofthe catalyst. 

Better diastereoselectivities were obtained when a-ketoamides of proline benzyl ester were treated with allyl halides in the presence of zinc dust and pyridinium p-toluenesulfonate (PPTS) at 4°C in a THF/water mixture. The chiral auxiliary could be removed from the purified amides, yielding a-hydroxyketones with excellent enantioselectivities (Waldmann, 1990), as depicted in Scheme 4.2. 

The efficient enantioselective alkylation of the P/y-unsaturated ester 39 was achieved1351 by use of the N-anthracenylmethyl catalyst 12 (R=benzyl, X=Br) together with CsOH-H20 under phase transfer conditions analogous to those in the alkylation of the O Donnell imine 23, as shown in Scheme 13. The enantioselectivity of the alkylation correlates with Hammett o constants, and the N,N-dimethylamino substituents in 39 showed the most effective enantioselectivity. The tight ion pair in which the enolate... 

Asymmetric reduction of ketones. Pioneering work by Ohno et al. (6, 36 7, 15) has established that l-benzyl-l,4-dihydronicotinamide is a useful NADH model for reduction of carbonyl groups, but only low enantioselectivity obtains with chiral derivatives of this NADH model. In contrast, this chiral 1,4-dihydropyridine derivative (1) reduces a-keto esters in the presence of Mg(II) or Zn(II) salts in >90% ee (equation I).1 This high stereoselectivity of 1 results from the beneficial effect... 

Scheme 2.41 Enantioselective intramolecular 1,4-addition ofenyne carbamate ester 125. Bn = benzyl.

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