Chiral auxiliary lactate

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. 

The Davies group has described several examples of a rhodium-catalyzed decomposition of a diazo-compound followed by a [2+1] cycloaddition to give divinyl cyclopropanes, which then can undergo a Cope rearrangement. Reaction of the pyrrol derivative 6/2-51 and the diazo compound 6/2-52 led to the tropane nucleus 6/2-54 via the cyclopropane derivative 6/2-53 (Scheme 6/2.11) [201]. Using (S)-lactate and (R)-pari lolaclorie as chiral auxiliaries at the diazo compound, a diastereoselectivity of around 90 10 could be achieved in both cases. 

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... 

The diastereoselectivity of the tropanes 1062 obtained from vinyldiazomethanes 1061 containing (/ )-pantolactone as the chiral auxiliary and various pyrroles (Equation 251) was roughly parallel to the results observed with the (5)-lactate auxiliary and ranged from 37% to 78% de <1997JOG1095>. 

Use as a Chiral Auxiliary. (5)-Ethyl lactate has been used as a chiral auxiliary in a variety of simple Diels-Alder reactions. As the fumaric acid diester, the de employing cyclopentadiene can almost be completely reversed by addition of Titanium(IV) Chloride (eq 8). In general, superior de values are achieved using (R)-Pantolactone in this context, and also for base-mediated addition to ketenes. ... 

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). 

Finally, acyclic primary alcohols have proved to be less efficient than cyclic secondary alcohols28, even with bulky anchoring substituents. Ethyl lactate, when employed as a chiral auxiliary for the acrylate 15, results in an inversion of the sense of induction according to the nature of the Lewis acid used to promote its addition to cyclopentadiene (9)29. 

Chiral ( >2-cyanocinnamates 16 bearing ethyl (.S i-lactate and (7 )-pantolactone as the chiral auxiliary are very efficient dienophiles in the asymmetric Dicls-Alder reaction with cyclopentadiene, opening up a route to the synthesis of cycloaliphatic atnino acids96. 

Exceptional are cyciopropanations with phenylethenyl-substituted diazoacetate 6 bearing a (R)-pantolactone unit as chiral auxiliary. The optimized rhodium(II)-catalyzed reaction of this diazo compound with phenylethene provides the cyclopropanecarboxylate 7 with a d.r. of 98.5 1.5. Recrystallization affords diastereomerically pure 7 which can be transformed into the enantiomerically pure (1 /< .2R )-1-amino-2-phenylcyclopropane carboxylic acid. Use of the corresponding (S)-lactates allows entry into the enantiomeric series105. This method was also applied to the enantioselective preparation of tropanes106... 

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... 

When lactate is used as a chiral auxiliary, the proximity of the enolic hydroxyl group and the carboxyl of the lactate induces an interaction between the functional groups in the photodienol. Therefore, a surprising solvent effect, and even a reversal of the diastereoselectivity with the content of 2-propanol in water, was reported [53]. Except for lactate 8f in methanol and 2-propanol/water mixtures, it was possible to correlate the chirality of the new asymmetric center with the configuration of the lactyl chiral auxiliary. When (S)-lactyl derivatives were examined, models indicated that the S-configuration of the new chiral center can be deduced from a sterically easier approach of the carboxylate group at the re face of the a-carbon of the dienol. 

Alkylation of lactates is not possible directly, since any enolate formation would destroy the chirality at the asymmetric center. This can be circumvented without use of a chiral auxiliary by employing the self-reproduction of chirality approach of Seebach, which incorporates lactic acid into a dioxolane ring and takes advantage of the bulky R group at the newly formed stereo center at C-2 to direct alkylation to the C-5 carbon. 

Fig. 26 Preferential binding of one enantioface of an arene induced by a lactate chiral auxiliary...

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

An efficient method for the asymmetric synthesis of tropanes was developed by using chiral auxiliaries (Tables 13 and 14). A wide range of tropanes were prepared in 30-85% yield and 25-79% de. Either enantiomeric series of tropanes can be prepared by using either (5)-lactate (Table 13) or (/ )-pantolactone (Table 14) as the chiral... 

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). ... 

The aldol reaction with the lactate derivative was applied to the synthesis of citreoviral 78 (Scheme 8.12). The enolate of 72 was reacted with unsaturated aldehyde 73 to yield a,(3-dihydroxy-7,8-unsaturated imide 74 in a stereoselective manner. Adduct 74 was subjected to iodolactonization to accompany the removal of the chiral auxiliary to give 75 as a single isomer. Debenzylation was followed by etherification with the tertiary alcohol to provide the highly substituted furan 77 having all the chiral centers of the target molecule. The additional four-step sequence afforded citreoviral 78. 

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. 

At the time, many unsuccessful attempts were made to improve the selectivity of the mismatched anti aldol reaction mentioned above, outlining the limitations of some chiral ligands or auxiliaries at overcoming inherent substrate bias in anti aldol reactions. Since the completion of this work, we have introduced the lactate-derived ketones (/ )- and (S)-39, which should now allow the stereoselective synthesis of the ebelactones. As shown in Scheme 9-75, each enantiomer of the parent ketone acts as a propionate equivalent with a covalently attached auxiliary which will overturn the facial bias of most aldehydes [27, 28]. 

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. 

Piva et al. have established removable chiral tethers that attach an alkene to an enone and render the intramolecular [2-1-2]-photocycloaddition between these groups highly diastereoselective. Chiral a-and P-hydroxy acids such as (S)-lactic acid, (S)-phenyllactic acid, or (S)-mandelic acid proved to be highly effective auxiliaries. Butenyl lactate 1 was converted regioselectively to the straight adduct 2. The diastereoselectivity reached 94% DE at -40°C, albeit with a reduction in yield. At -20 C, 92% DE and 78% yield were obtained (Scheme 2). 

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