Ethyl L-lactate

Discuss possible procedures for resolution of ethyl D,L-lactate (ethyl 2-hy-droxypropanoate bp 155°) into ethyl d-lactate and ethyl L-lactate. 

Rhlid el a I.2 4 have tried to exploit these results technologically by preparing 2-(l-hydroxyethyl)-2-thiazoline by microbial fermentation (cysteamine, ethyl L-lactate, and D-glucose with bakers yeast) and incorporating it into a pizza recipe (5 mg per 50 g raw dough), leading to increases in the roasted, toasted, popcorn-like aromas. 

Ethyl L-(-)-lactate was purchased from Fluka AG, Buchs, Switzerland and was used directly. Checkers found that fresh ethyl lactate purchased from Fluka 1s only 97-98S ee, by 19F NMR spectroscopy on the Mosher ester. 

Ethyl L-(-)-lactate Lactic acid, ethyl ester, L- (8) Propanoic acid, 2-hydroxy-, ethyl ester, (S)- (9) (687-47-8)... 

The reaction of ethyl L-lactate with A -benzyloxycarbonylbenzamide under Mitsunobu conditions produces 109 stereospecifically. Removal of the Cbz protecting group under acidic conditions gives (R)-( — )-A -benzoylalanine ethyl ester (110) [39], A host of differentially A,A-diprotected (R)-alanines (111) can be prepared analogously by reaction of 2 with an imidodicarbonate or tosylcarbamate [40]. The enantiomeric excess in Mitsunobu products 111 exceed 95%. 

Active methylene groups undergo Mitsunobu reactions with alcohols. Thus, when ethyl cyanoacetate is reacted with ethyl L-lactate, diethyl 2-cyano-3-methylsuccinate (113) is formed in 61% yield [42]. Acidic hydrolysis furnishes (5)-( — )-methylsuccinic acid (114) in 29% yield with an optical purity of 99% [43]. 

Lofexidine (143), a weakly active oc2-adrenoceptor agonist, has been synthesized in 8 steps starting from ethyl L-lactate according to the route shown in Scheme 21 [30]. The key reaction in the synthesis is that of tosylate 120b with 2,6-dichlorophenol. The transformation occurs with nearly complete inversion of configuration. The cardiovascular activity of 143 is approximately one-tenth that of the corresponding ( — )-enantiomer 89. 

The asymmetric center of 120b can be inverted with carbon nucleophiles, as demonstrated by the synthesis of 1-ethyl ( S)-( — )-2-methylsuccinate (145) [52]. The reaction of 120b with sodium di- r -butylmalonate gives triester 144 with total inversion of configuration. Hydrolysis and decarboxylation furnishes the monoacid 145 (99% ee) in 54% overall yield from ethyl L-lactate. 

R)-( + )-Methyloxirane, a useful chiral intermediate, has been employed in the synthesis of a variety of natural products. It is readily prepared in multi-gram quantities from ethyl L-lactate via tosylate 120b [53,54]. Reduction of the ester proceeds quantitatively with diborane over a period of 5 days to afford ( S)-( + )-propane-l,2-diol 2-tosylate (146). Cyclization with KOH gives epoxide 147 with 97% inversion of configuration. 

The properties of cesium salts can be taken advantage of to convert (5)-ethyl lactate to its / -enantiomer without racemization [63]. Treatment of mesylate 156b with cesium propionate gives (7 )-(acyloxy)propionate (170) in good yield [72]. Titanium-mediated transesterification of the ( S)-enantiomer of 170 under essentially neutral conditions has been reported to give ethyl L-lactate (60% yield) with no racemization [64]. Application of this methodology to (/ )-170 should give ethyl D-lactate (171). 

In an improved preparation of (R)-( + )-methyloxirane (147), the ester group of 156b is reduced with AIH3 within 30 minutes to give (5)-2-(mesyloxy)-l-propanol (183). Cyclization with potassium hydroxide furnishes the desired epoxide in 72% overall yield fi om 156b and 71% overall yield from ethyl L-lactate [69]. 

Ethyl-2-methyl-l,6-dioxaspiro[4.5]decane is a pheromone produced by two varieties of bees, Parvespula vulgaris L. and Andrena haemorrhoa F. The 27 , 57 , 77 -isomer (188) has been synthesized using 147, ultimately derived from ethyl L-lactate, to supply the chiral stereocenter at C-2 (Scheme 26) [19]. The second chiral intermediate 185 is derived from (5)-( — )-malic acid. 

The overall yield in the sequence is 42.6% starting from 184, and the optical purity of the final product is 96%. The remaining three possible stereoisomers of 188 have been prepared using (5)-methyloxirane, also available from ethyl L-lactate (see Section 1.4.4), and the enantiomer of 185, available from ( S)-malic acid. 

Esterification of 123 with diazoethane furnishes ethyl (5)-2-acetoxypropionate (222). Alternatively, direct treatment of ethyl L-lactate (2) with acetyl chloride in benzene gives 222 in slightly higher yield [81]. 

Benzylation of lactic acid esters can be accomplished by two methods. Treatment of methyl or ethyl L-lactate with benzyl bromide and silver oxide provides the corresponding (5)-2-ben-zyloxypropionates 271 with high optical purity [92,93]. Use of standard basic conditions (NaH, DMF) results in considerable racemization (50-75% ee). 

Alternately, ethyl L-lactate can be benzylated without racemization using benzyl tri-chloroacetimidate [94,95] however, this reagent is rather expensive. 

Protection of ethyl L-lactate with a BOM group is readily accomplished with chloromethyl benzyl ether in the presence of Hunig s base [100,101]. 

The 1-ethoxyethoxy protecting group is attached to ethyl L-lactate by treating 2 with ethyl vinyl ether in the presence of either 36% HCl [107] or trifluoroacetic acid [108]. 

If malonate 313 is hydrolyzed and decarboxylated without removing the protecting group, ( S)-4-benzyloxy-3-methylbutanoic acid (317) is produced in 30% overall yield from ethyl L-lactate (2). 

One of the earlier syntheses of ( S)-( — )-methyloxirane (40) utilizes the EE protecting group as an integral part of the process [108]. The 5-step sequence, starting from ethyl L-lactate, proceeds in 46% overall yield and gives 40 with high optical purity. 

One of the four stable stereoisomers of 7-ethyl-2-methyl-l,6-dioxaspiro[4.5]decane, a bee pheromone, has been synthesized using 40 according to the route shown in Scheme 44. The IS, 5S, 7 S-isomer 328, derived from both ethyl L-lactate and malic acid (precursor for 325), is produced in good yield with an optical purity of 96% [19]. 

The framework of the macrolide can be assembled from the two segments 342 and 348, each of which is derived from ethyl L-lactate via lactamide 11b (Schemes 46 and 47). 

A related family of 3-amino-2,3,6-trideoxyhexoses, L-daunosamine (386), the carbohydrate component of anticancer anthracycline antibiotics, L-vancosamine (387), the carbohydrate component of the antibiotics vancomycin and sporaviridin, and D-ritosamine (388), the enantiomer of the carbohydrate component of the antibiotic ristomycin, has been prepared from ethyl L-lactate [119]. 

Ethyl L-lactate can be protected with a TBPS group by reaction with rer -butyldiphenylsilyl chloride and imidazole in either tetrahydrofuran [134] or DMF [135]. Alternatively, using DBU as the base in methylene chloride furnishes 427 in 100% yield [140]. 

Using standard conditions for THP-protection, ethyl L-lactate is converted to the tetrahydro-2-pyranyloxy derivative 450 by reaction with dihydropyran in the presence of acid catalyst [141,142]. 

An efficient method for tritylation of ethyl L-lactate is the treatment of 2 with triphenylmethyl chloride and DBU in methylene chloride [140]. This procedure is general for tritylation of secondary alcohols, that under standard conditions react slowly or not at all. 

The key reaction, addition of Grignard reagent 633 to aldehyde 632, proceeds at —100 °C to give adduct 634 with 95 5 syn diastereoselectivity [116]. The overall yield of the four-step sequence starting from ethyl L-lactate (2 — 632 —> 634 —> 635) is 31%. 

The preparation of MOM-protected lactaldehyde 658 parallels that of the MEM derivative. It can be obtained in a two-step sequence in which lactate 377 is initially reduced to the propanol 657 and then oxidized to the aldehyde under Swem conditions [199] or with Collins reagent [100]. Overall yields starting from ethyl L-lactate (2) average about 50%. Alternatively, ester 377 can be reduced directly to aldehyde 658 (52% yield) with diisobutyl-aluminum hydride at —78 °C [120,200]. 

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