Benzyl ( R )-2-( Acetylthio ) Propanoate : A Promising Sulfur Isoster of ( R )-Lactic Acid and Ester Precursors

In this paper, an accessible chiral pool synthesis of benzyl (R)-2-(acetylthio)propanoate (acetylthiolactate), which is less odorous than the methyl or ethyl analogue, was performed through a clean SN2 displacement reaction using available AcSK with tris[2-(2-methoxyethoxy)]ethylamine (TDA-1), starting from commercially available benzyl (S)-lactate in 76%, 94% ee (2 steps). Deprotection of the acetyl group using N,N-dimethylethylenediamine afforded benzyl (R)-2-sulfanylpropanoate in 93% yield with 90% ee. These two sulfur-containing benzyl esters were sufficiently odorless to be purified by column chromatography. Direct HPLC analysis was applied to determine the enantiomeric excess without thiazolidin-4-one derivatizations. A complementary debenzylation of benzyl (R)-2-(acetylthio)propanoate was also performed using HBr/AcOH to afford (R)-2-(acetylthio)propanoic acid without critical racemization in 92% yield with 92% ee.


Introduction
Synthetic chemistry of optically pure secondary thiols as the isoster of the corresponding chiral alcohols has attracted much attention [1,2].Chiral 2-sulfanyl (classically, α-mercapto) carboxylic acids, and esters are well-recognized synthetic building blocks for distinctive derivatives of chiral 2-hydroxycarboxylic acids and esters in natural products and pharmaceutical syntheses.Among them, chiral 2-sulfanylpropanoic acid and esters 1 (thiolactic acid and esters) serve as the most fundamental chiral synthons (Figure 1).In this paper, we report a straightforward and accessible synthesis of novel benzyl (2R)-2-(acetylthio)propanoate [(R)-2] starting from inexpensive and commercially available benzyl (S)-lactate through mesylation and a clean S N 2 displacement reaction using available AcSK with tris[2-(2-methoxyethoxy)]ethylamine (TDA-1) [3].In addition, convenient direct HPLC analysis was performed to determine the accurate optical purities of (R)-2 and their analogues.
Due to the demand, several synthetic methods to access 1 have been developed to date.Scheme 1 shows the most traditional synthesis of (R)-1a starting from chiral alanine, developed by Owen's [21] and Kellogg's groups [22]; stereoretentive diazotization-chlorination; SN2 displacement with AcSCs (generated in situ from AcSH and Cs2CO3); and deacetylation sequences.The addressed yields are referred from Townsend and co-workers' total synthesis of (R)-thiolactomycin [9].However, this reliable method requires a somewhat tedious step for in situ generation of odorous and hygroscopic AcSCs from AcSH and Cs2CO3, and results in moderate overall yield.Another notable synthesis is copper-catalyzed enantioselective carbenoid insertion to αdiazopropanoate; this method afforded the desired benzyl ester 5 with 77% ee using a chiral bisoxazoline ligand [23].In connection with our continuing studies on process chemistry and biologically active sulfur-and nitrogen-containing heterocyclic compounds [24][25][26][27], we planned to develop a practical and robust synthesis of chiral building blocks 1. Chiral acid and esters 1 have two characteristic synthetic utilities.One is the chiral template methodology [17] using 1,3-oxathiolan-4-ones derived from 1, which involves distinct self-regeneration of the stereocenter [18].This protocol was successfully applied for the asymmetric synthesis of (5R)-thiolactomycin and its analogues [9, 19,20].Another is a thiazolidin-4-one type chiral ligand derived from 1, which was utilized for a Cu(I)-catalyzed asymmetric conjugate addition to enones, developed by Feringa's group [20].
Due to the demand, several synthetic methods to access 1 have been developed to date.Scheme 1 shows the most traditional synthesis of (R)-1a starting from chiral alanine, developed by Owen's [21] and Kellogg's groups [22]; stereoretentive diazotization-chlorination; SN2 displacement with AcSCs (generated in situ from AcSH and Cs2CO3); and deacetylation sequences.The addressed yields are referred from Townsend and co-workers' total synthesis of (R)-thiolactomycin [9].However, this reliable method requires a somewhat tedious step for in situ generation of odorous and hygroscopic AcSCs from AcSH and Cs2CO3, and results in moderate overall yield.Another notable synthesis is copper-catalyzed enantioselective carbenoid insertion to αdiazopropanoate; this method afforded the desired benzyl ester 5 with 77% ee using a chiral bisoxazoline ligand [23].In connection with our continuing studies on process chemistry and biologically active sulfur-and nitrogen-containing heterocyclic compounds [24][25][26][27], we planned to develop a practical and robust synthesis of chiral building blocks 1.Another notable synthesis is copper-catalyzed enantioselective carbenoid insertion to α-diazopropanoate; this method afforded the desired benzyl ester 5 with 77% ee using a chiral bisoxazoline ligand [23].In connection with our continuing studies on process chemistry and biologically active sulfur-and nitrogen-containing heterocyclic compounds [24][25][26][27], we planned to develop a practical and robust synthesis of chiral building blocks 1.

Results
Our previous report described the synthesis of 1 as well as the related α-sulfanyl succinate and mandelate and their accurate HPLC optical purity determinations by derivatization under nearly neutral conditions [Ti(Oi-Pr) 4 /N-benzylidenemethylamine] to thiazolidin-4-ones [3].However, in the case of 1, this method required the isolation of methyl acetylthiolactate and methyl thiolactate, both of which have a highly unpleasant odor due to their high volatility.To address this problem, we investigated an alternative protocol using benzyl analogues.Scheme 2 outlines the reaction sequence.Cheap and available benzyl (S)-lactate 3 was converted to benzyl (S)-methanesulfonate 4.
The key clean S N 2 displacement reaction of 4 was conducted using commercially available AcSK-an odorless, less hygroscopic, easy-to handle solid in bench-top procedures-and compared with liquid AcSH and Cs 2 CO 3 [22].Condition A (TDA-1, tris[2-(2-methoxyethoxy)]ethylamine additive, AcOEt solvent) is slightly superior to conventional condition B (no additive, DMF solvent) with regard to yield, enantiomeric excess, and well-equalized suspension formation during the reaction.TDA-1 is an inexpensive and less toxic cryptand modified for 18-crown-6.

Results
Our previous report described the synthesis of 1 as well as the related α-sulfanyl succinate and mandelate and their accurate HPLC optical purity determinations by derivatization under nearly neutral conditions [Ti(Oi-Pr)4/N-benzylidenemethylamine] to thiazolidin-4-ones [3].However, in the case of 1, this method required the isolation of methyl acetylthiolactate and methyl thiolactate, both of which have a highly unpleasant odor due to their high volatility.To address this problem, we investigated an alternative protocol using benzyl analogues.Scheme 2 outlines the reaction sequence.Cheap and available benzyl (S)-lactate 3 was converted to benzyl (S)-methanesulfonate 4. The key clean SN2 displacement reaction of 4 was conducted using commercially available AcSK-an odorless, less hygroscopic, easy-to handle solid in bench-top procedures-and compared with liquid AcSH and Cs2CO3 [22].Condition A (TDA-1, tris[2-(2-methoxyethoxy)]ethylamine additive, AcOEt solvent) is slightly superior to conventional condition B (no additive, DMF solvent) with regard to yield, enantiomeric excess, and well-equalized suspension formation during the reaction.TDA-1 is an inexpensive and less toxic cryptand modified for 18-crown-6.
Benzyl (R)-acetylthioester 2 was considerably less odorous than the corresponding methyl or ethyl acetylthioester and, therefore, readily purified by column chromatography.Mild deacetylation of 2 with N,N-dimethylethylenediamine afforded benzyl (R)-2-sulfanylpropanoate (5) in 93% yield with 90% ee.Complementary debenzylation of 2 afforded (R)-2-(acetylthio)propanoic acid (6) upon treatment with HBr/AcOH in 92% yield, also without significant racemization (92% ee).Catalytic hydrogenation to remove the benzyl group failed to proceed (no reaction or decomposition) in any of the cases examined [H2, 10% Pd/C; TBS-H, Pd(OAc)2, Et3N; Et3SiH, Pd(OAc)2, Ph3P; PdCl2].The enantiomeric purity determination of 2 and 5 is a crucial subject.Two methods of determining the optical purity have been reported to date.The seminal method was developed by Kellogg and Feringa's group utilizing 13 C and 31 P-NMR determination techniques of phosphonodithiolate derivatives and/or chiral shift reagents [28].The other more accurate method utilized the neutral derivatization of 2-sulfanylcarboxylic acids and esters to thiazolidin-4-ones, which were subjected to HPLC analyses [3,11].Notably, direct HPLC analysis of 2 and 5 to determine the enantiomeric excess was performed with the aid of UV detection of the benzyl group; derivatization to the corresponding thiazolidin-4-ones was omitted.

General
All reactions were carried out in oven-dried glassware under an argon atmosphere.Flash column chromatography was performed with silica gel Merck 60 (230-400 mesh ASTM, Tokyo, Japan).TLC analysis was performed on 0.25 mm Silicagel Merck 60 F254 plates (Tokyo, Japan).Melting points were determined on a hot stage microscope apparatus (AS ONE, ATM-01, Tokyo, Japan) and were uncorrected.NMR spectra were recorded on a JEOL DELTA 300 or JEOLRESONANCE ECX- The enantiomeric purity determination of 2 and 5 is a crucial subject.Two methods of determining the optical purity been reported to date.The seminal method was developed by Kellogg and Feringa's group utilizing 13 C and 31 P-NMR determination techniques of phosphonodithiolate derivatives and/or chiral shift reagents [28].The other more accurate method utilized the neutral derivatization of 2-sulfanylcarboxylic acids and esters to thiazolidin-4-ones, which were subjected to HPLC analyses [3,11].Notably, direct HPLC analysis of 2 and 5 to determine the enantiomeric excess was performed with the aid of UV detection of the benzyl group; derivatization to the corresponding thiazolidin-4-ones was omitted.

General
All reactions were carried out in oven-dried glassware under an argon atmosphere.Flash column chromatography was performed with silica gel Merck 60 (230-400 mesh ASTM, Tokyo, Japan).TLC analysis was performed on 0.25 mm Silicagel Merck 60 F 254 plates (Tokyo, Japan).Melting points were determined on a hot stage microscope apparatus (AS ONE, ATM-01, Tokyo, Japan) and were uncorrected.NMR spectra were recorded on a JEOL DELTA 300 or JEOLRESONANCE ECX-500 spectrometer (Tokyo, Japan), operating at 300 MHz or 500 MHz for 1 H-NMR and 75 MHz or 120 MHz for 13 C-NMR.Chemical shifts (δ ppm) in CDCl 3 were reported downfield from TMS (=0) for 1 H-NMR.For 13 C-NMR, chemical shifts were reported in the scale relative to CDCl 3 (77.00ppm) as an internal reference.IR Spectra were recorded on a JASCO FT/IR-5300 spectrophotometer (Tokyo, Japan).Mass spectra were measured on a JEOL JMS-T100LC spectrometer (Tokyo, Japan).