(S)-Ethyl Lactate

(S)-(R = Et)

[687-47-8]  · C5H10O3  · (S)-Ethyl Lactate  · (MW 118.15) (R)-(R = Et)

[97-64-3]  · C5H10O3  · (S)-Ethyl Lactate  · (MW 118.15) (S)-(R = Me)

[17392-83-5]  · C4H8O3  · (S)-Methyl Lactate  · (MW 104.12) (R)-(R = Me)

[27871-49-4]  · C4H8O3  · (S)-Ethyl Lactate  · (MW 104.12) (R)-(R = Bu)

[34451-18-8]  · C7H14O3  · (R)-t-Butyl Lactate  · (MW 146.21)

(chiral pool reagent for synthesis; occasionally used as a chiral auxiliary)

Alternate Name: ethyl L-(-)-lactate.

Physical Data: (S)-(R = Et) bp 154 °C, 69 °C/36 mmHg, d 1.031 g cm-3;20 (R)-(R = Et) bp 58 °C/20 mmHg, d 1.032 g cm-3;20 (S)-(R = Me) bp 40 °C/11 mmHg, d 1.086 g cm-3;25 (R)-(R = Me) bp 58 °C/19 mmHg, d 1.091 g cm-3;20 (R)-(R = Bu) bp 77 °C/10 mmHg, d 0.974 g cm-3.27

Solubility: sol water, alcohols, ethers, THF, and common organic solvents.

Form Supplied in: liquid; commercially available.

Use as a Chiral Pool Reagent.

(S)-Ethyl lactate has been extensively used as a chiral pool reagent, often via transformation into a diverse array of simple, enantiomerically pure analogs. Principal among these are a variety of O-protected (S)-2-hydroxypropanals (eq 1).

These have been prepared by various combinations of straightforward steps including ester to amide conversion, alcohol protection, direct reduction of the ester or amide to the aldehyde group, and reduction of the ester to the alcohol followed by reoxidation to the aldehyde. The sensitivity of the (S)-propanals to epimerization has been of paramount concern. One of the best procedures which avoids racemization and has been run on a preparative scale is noted (eq 2).1

Subsequent reduction also affords (S)-2-benzyloxypropanol in 89% yield. NMR assay of the (R)- and (S)-Mosher esters indicated no racemization over the sequence. Synthesis via oxidation of (S)-benzyloxypropanol (eq 3) provides the benzyloxypropanal with <8% racemization.2

Attempted formation of the benzyl ether of (S)-ethyl lactate with NaH/BnBr results in considerable racemization (50-75% ee). This racemization is obviated by use of the amide analog noted in eq 2. Diisobutylaluminum Hydride has been used to convert the ester directly to the aldehyde employing the methoxymethyl,3,4 benzyl,2,5 2,6-dichlorobenzyl,6 t-butyldiphenylsilyl,7 benzyloxymethyl,8 THP,9 trityl10 and TBDMS11 protecting groups. Protected (S)-2-hydroxypropanals have been used in synthetic studies relating to sugars,12-15 amino sugars,16 thiotetronic acids,17 antimycin-A3,18 rhodinose,19 aplysiatoxin via the (R)-lactate,20 (-)-sarracenin,21 and for preparation of enantiomerically pure 1-methyl-2-alkenyl-N,N-diisopropylcarbamates from the (R)- and (S)-lactates.22

(S)-Ethyl lactate has also been used as a ready source of (S)-propane-1,2-diol and (S)-methyloxirane (eq 4).23,24 These compounds have been used for preparation of numerous natural products including nonactin,25 sulcatol,26 recifeiolide,27 methyl-1,6-dioxaspiro[4,5]decanes, the pheromone components of Paravespula vulgaris,28 and the rhynchosporosides.29 The (S)-oxirane has also been used in the synthesis of chiral macrocyclic poly(ether diester)ligands.30 A convenient procedure for preparation of the (R)-methyloxirane via mesylate activation, reduction, and internal inversion has been reported.31

A variety of inverted analogs of (S)-ethyl lactate have been prepared by standard activation displacement procedures. Included are the (R)-propionyloxypropionate (mesylation/EtCO2Cs-DMF);32 azide (Mitsunobu conditions);33,34 aryloxy ethers (mesylation/aryl oxide);35 chloride (SOCl2-DMF);36 bromide (sulfonation/MgBr2);37 mercapto analogs (Mitsonobu conditions);38,39 amino analogs (triflate/amine);40 hydroxylamines;41,42 and selenides.43

Protected (S)-ethyl lactate cleanly acylates methyllithium to afford the 2-butanone with essentially complete enantiomeric fidelity and in nearly quantitative yield. Various diastereoselective constructions were achieved by nucleophilic addition to the ketone (eq 5).44 For example, addition of vinyllithiums, followed by acetal formation and Lewis acid-mediated rearrangement, provided a ready entry into the indicated 3-acyltetrahydrofurans.

(S)-Ethyl lactate has been used to prepare (S)-2-methyloxetane in modest yield with <0.5% racemization by a series of standard transformations (eq 6).45

Other small chiral molecules have also been prepared by straightforward transformations (eq 7).46

(S)-Ethyl lactate has also been used as a chiral fragment for numerous other studies. Included are synthetic efforts relating to salenomycin,47 (-)-biopterin,48 (+)-polyoxamic acid,49 jaspamide,50 the enantiomeric 2-pentanols,51 pumilitoxin B,52,53 D-ristosamine,54 protomycinolide IV,55 and tirandamycin.56

Use as a Chiral Auxiliary.

(S)-Ethyl lactate has been used as a chiral auxiliary in a variety of simple Diels-Alder reactions.57 -60 As the fumaric acid diester, the de employing cyclopentadiene can almost be completely reversed by addition of Titanium(IV) Chloride (eq 8).61 In general, superior de values are achieved using (R)-Pantolactone in this context, and also for base-mediated addition to ketenes.62

(S)-Ethyl lactate was used for diastereocontrol and asymmetric transmission in a sequential 2,3-Wittig-oxy-Cope rearrangement, affording product in 91% ee (eq 9).63,64 Excellent asymmetric induction has also been noted in the Lewis acid-mediated ene reaction of (S)-ethyl lactate-derived intermediates (eq 10).65

(S)-Ethyl lactate has been used to enantioselectively protonate the indicated enolate at -100 °C to afford the (R)-ketone in 73% yield and 73% ee (eq 11).66

Applications to Products of Commercial Interest.

(S)-Ethyl lactate has been incorporated in chiral syntheses of (S)-2-arylpropionic acids, an important class of nonsteroidal anti-inflammatory agents, including ibuprofen and naproxen (eq 12).67 -69 These syntheses, though elegant in concept, are unlikely to compete with existing industrial methods for production of the (S) enantiomers of these drugs.

(S)-Ethyl lactate has also been used to synthesize the important 4-acetoxyazetidinone intermediate, crucial to numerous carbapenem syntheses. The key step in its use was the diketene addition to the (S)-lactaldehyde imine, which in the best case proceeded in 67% yield with a 10:1 ratio of diastereomers (eq 13).70,71

Other applications to b-lactam syntheses have been reported.72-74

Related Reagents.

Ethyl Mandelate; (R)-Pantolactone.

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Edward J. J. Grabowski

Merck & Co., Rahway, NJ, USA

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