Chiral auxiliaries lactate esters

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

Enantioselective carbenoid cyclopropanation of achiral alkenes can be achieved with a chiral diazocarbonyl compound and/or chiral catalyst. In general, very low levels of asymmetric induction are obtained, when a combination of an achiral copper or rhodium catalyst and a chiral diazoacetic ester (e.g. menthyl or bornyl ester ) or a chiral diazoacetamide ° (see Section 1.2.1.2.4.2.6.3.3., Table 14, entry 3) is applied. A notable exception is provided by the cyclopropanation of styrene with [(3/ )-4,4-dimethyl-2-oxotetrahydro-3-furyl] ( )-2-diazo-4-phenylbut-3-enoate to give 5 with several rhodium(II) carboxylate catalysts, asymmetric induction gave de values of 69-97%. ° Ester residues derived from a-hydroxy esters other than ( —)-(7 )-pantolactone are not as equally well suited as chiral auxiliaries for example, catalysis by the corresponding rhodium(II) (S )-lactate provides (lS, 2S )-5 with a de value of 67%. 

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]. 

Other types of functionalized enantiopure alcohols also make good chiral auxiliaries. Esters of commercially available methyl or ethyl (S)-lactates 1.15 [156] and (i )-pantolactone 1.16 [157, 158] are popular. The (5)-hydroxysuccinimide derivative 1.17, easily obtained from (S)-malic acid [158], provides access to the enantiomers of the products formed in the reactions of (f )-pantolactone 1.16. 

Pete and coworkers [1000, 1001] have irradiated a,P-ethylenic esters of enantiopure alcohols, and the intermediate dienols that form are protonated either with AyV-dimethylethanol at -35°C in hexane [1001] or with i-PrOH or terf-BuOH [1000], The chiral auxiliaries are diacetoneglucose 1.48 or (S)-ethyl lactate 2.1 (R = Me, R = Et), or better yet the corresponding add (Figure 4.9). The cleavage of the chiral auxiliary is accomplished by treatment with PhCH20H/Ti(0/-Pr)4 or by mild hydrolysis. After the subsequent reaction with diazomethane, nonracemic benzyl or methyl a-alkylated-P.y-unsaturated esters are obtained with high enantiomeric excesses (Figure 4.9). 

The lactone of 2,4-dihydroxy-3,3-dimethylpentanoic acid (known as pantolactone) has been successfully employed as a chiral auxiliary in several D-A reactions. For example, in conjunction with TiCl4, it provides a 92% de in the reaction of 2,3-dimethylbutadiene with a-cyanocinnamic acid. The diastereoselectivity is consistent with a chelated structure similar to that shown above for acryloyl lactate. In the absence of TiCl4, this same ester gives a 64% de of the opposite configuration. This... 

Impressively short is a total synthesis by Ian Paterson [281], who uses a lactate ester as chiral auxiliary. This is subsequently converted into a ketone via a Grignard reaction with its Weinreb amide. The boron-mediated aldol reaction, after an oxidative work-up, gives the aldol with a diastereoselectivity of >98 %. Since also the reaction with propionaldehyde shows the same diastereoselectiv-... 

Alternatively, (trimethylenemethane)iron complexes can be synthesized by disproportionation of tricarbonyl(2-methallyl)ironJ Enantiomerically pure tricarbonyl-(trimethylenemethane)iron complexes can be obtained by resolution of the racemic mixture via diastereomeric esters or amides. (5)-(-)-Ethyl lactate and (/ I)-(+)-a-methyl-benzylamine are employed as resolving reagents for this piupose. The chiral auxiliaries can be removed by a variety of reagents leaving the (trimethylenemethane)iron fragment unaffected. Treatment of both the corresponding Boc-protected amides and the chiral esters with diisobutylaluminum hydride (DIBAL) or methyllithium provides the primary or tertiary alcohols, respectively. Saponification of the ester with lithium hydroxide in methanol and subsequent acidification of the mixture affords the methyl ester. Treatment of the ester with triethylsilane leads to complete reduction of the functionality to leave a methyl group (Scheme 4—85). ... 

Charlton, J. L., Pham, V. C., and Pete, J. R, Lactate as chiral auxiliary in asymmetric photodeconjugation of unsaturated esters, Tetrahedron Lett., 33, 6073,1992. 

In some examples, the stereochemistry of radical reactions was controlled by chiral carbohydrate auxiliaries. As a radical counterpart to the ionic conjugate additions discussed above, Garner et al. [169] prepared carbohydrate linked radicals that were reacted with a,P-unsaturated esters. The radical precursor, the carboxylic acid 256, generated by the addition of ( Sj-methyl lactate to tri-O-benzyl-D-glucal and subsequent ester hydrolysis, was decarboxylated by Barton s procedure (Scheme 10.84) [170]. Trapping of the chiral radical 258 with methyl acrylate furnished the saturated ester 259 in 61% yield and with high diastereoselectivity (11 1). The auxiliary caused a preferential addition to the si-facQ of radical 258, probably due to entropic effects. The ester 259 was transformed in acceptable yield to the y-butyrolactone 261 by reductive removal of the thiopyridyl group followed by acid hydrolysis. 

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