New routes to α-amino acid β,γ-thioenol ether derivatives

Article abstract of DOI:10.1081/SCC-120002014

Racemic derivatives of α-amino acid β,γ-thioenol ethers have been synthesized from homoserine through a γ-elimination on a sulfoxide derived from aspartaldehyde. Optically active derivatives were efficiently prepared from L-methionine by a Pummerer like r

Full text of DOI:10.1081/SCC-120002014

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
NEW ROUTES TO α-AMINO ACID β,γ-THIOENOL
ETHER DERIVATIVES
Patrick Meffre & Philippe Durand
To cite this article: Patrick Meffre & Philippe Durand (2002) NEW ROUTES TO α-AMINO ACID
β,γ-THIOENOL ETHER DERIVATIVES, Synthetic Communications, 32:2, 287-296, DOI: 10.1081/
SCC-120002014
To link to this article: http://dx.doi.org/10.1081/SCC-120002014
Published online: 16 Aug 2006.
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Date: 09 June 2016, At: 17:51

SYNTHETIC COMMUNICATIONS, 32(2), 287–296 (2002)
NEW ROUTES TO a-AMINO ACID
b,c-THIOENOL ETHER DERIVATIVES
Patrick Meffre* and Philippe Durand
Ecole Nationale Superieure de Chimie de Paris,
11, rue Pierre et Marie Curie,
75231 Paris Cedex 05, France
ABSTRACT
Racemic derivatives of a-amino acid b,g-thioenol ethers have
been synthesized from homoserine through a g-elimination on
a sulfoxide derived from aspartaldehyde. Optically active deri-
vatives were efficiently prepared from L-methionine by a
Pummerer like reaction.
a-Amino acid b,g-enol ethers 1 and their sulfur analogues 2 are com-
pounds of biological interest: they are possible pyridoxal phosphate depen-
dent enzyme inhibitors because of the presence of the double bond in the
b,g-position.1
Indeed, the oxygen analogues 1 have shown antibiotic activity.2 Both
types of compounds exhibit some antiproliferative activity because they act
as methionine analogues and inhibit S-adenosyl methionine transferase.3
(Scheme 1)
*Corresponding author. Fax: þ33 (0)1 43 25 79 75; E-mail: patmeffr@ext.jussieu.fr
287
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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Scheme 1.
While several satisfactory synthetic solutions have been described for
the a-amino acid b,g-enol ether derivatives 1,4 only two very similar path-
ways exist for the sulfur analogues 2 (R¼Me). Starting from achiral diethyl
acetamido malonate, the vinyl sulfide moiety is obtained by the elimination
of a methylsulfinyl group in the g-position (Scheme 2).5 Actually, various
proportions of the a,b-unsaturated isomers are obtained in this step: unlike
their oxygen analogues 1, compounds 2 are highly prone to isomerisation
into the more stable a,b-unsaturated analogues.5,6 The optically active deri-
vatives are obtained through enzyme catalysed acid or amino group depro-
tections. Therefore, overall yields are very low. The problems experienced by
the groups involved in the synthesis of derivatives 2 clearly show that it is a
real synthetic challenge.5a
Scheme 2.
In this paper, we describe two new routes to derivatives 2 from the
chiral pool: homoserine and methionine.
Racemic homoserine was first converted into the aspartaldehyde
derivative 3 following the literature procedure.4a,7 The precursor sulfoxide
5 was obtained in good yield through dithioacetal formation8 followed by

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289
sodium metaperiodate monooxidation. We have found optimal conditions
to perform the thermal elimination of the sulfoxide9 leading to the forma-
tion of the desired b,g-unsaturated a-amino acid derivatives 6 with a global
yield of 50% without detecting the formation of the a,b-unsaturated
isomers. (Scheme 3)
Nevertheless, the proceding route, although successful, is still
laborious.10
Scheme 3.
We have recently shown11 that L-methionine is a possible precursor to
optically active aspartaldehyde derivatives using a Pummerer like reaction12
(a regioselective a-chlorination to the sulfide using N-chlorosuccinimide)
followed by hydrolysis. Alternatively, we now report that optically active
2-amino-4-methylthio-3-butenoic acid (‘‘3,4-dehydro-L-methionine’’) deriva-
tives can be efficiently obtained from L-methionine using the same reac-
tion13 (Scheme 4).
Phthaloyl protection14 was chosen to avoid any amine participation.15
(N,O)-protected L-methionine 7 is treated with N-chlorosuccinimide in
carbon tetrachloride. When the crude mixture of a-chlorosulfide intermedi-
ates is heated in dimethylformamide (70ꢀC), the formation of the vinyl
sulfide 8 is observed resulting from acid catalysed dehydrochlorination12b,13

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MEFFRE AND DURAND
Scheme 4.
probably through the transient ionic species B in equilibrium with A in the
polar solvent dimethylformamide (Scheme 5).
Scheme 5.
After purification by silica gel chromatography, major (E ) isomer was
shown to have 90–91% ee based on chiral HPLC analysis (see experi-
mental part). The observed slight racemisation (compound 7 proved to be
96–98% ee11b) might be done to the well-known stereochemical instability of
these b,g-unsaturated a-amino acid derivatives.
In conclusion, the procedures described herein allow the efficient syn-
thesis of a-amino acids b,g-thioenol ethers derivatives with optimized steps.
The Pummerer strategy using L-methionine as starting material lead to the

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291
protected optically active unsaturated analogue ‘‘3,4-dehydro-L-methionine’’
very quickly and efficiently without any detectable double bond isomerisa-
tion using cheap and easily handled reagents. Deprotection and variation
study on the amino protecting groups as well as generalization to other
thioether derivatives of commercially available optically active homocys-
teine are under investigations in our laboratory.
EXPERIMENTAL
All solvents and reagents were used as purchased. CCl4 and DMFwere
stored over 4 A molecular sieves before use. Purifications by flash column
chromatography were performed using silica gel 60 0.04–0.063 mm
(230–400 mesh) (Merck ref 9385), and TLC using silica gel 60F254, layer
thickness 0.2 mm on aluminum sheets.
Melting points were determined on a Mettler FP 62 apparatus and are
corrected. Optical rotations were measured on a Perkin Elmer 241 polari-
meter in a 1 cm cell. IR spectra were obtained using a Nicolet 205 FT-IR
spectrometer. 1H and 13C NMR spectra were recorded on a Bruker AM 200
spectrometer. Chemical shifts are reported as d values (ppm) relative to
internal tetramethylsilane.
Chiral HPLC analysis was performed using a 25 cm  0.46 cm Chiracel
OJ column from Daicel.
Benzyl (2RS )-2-Benzyloxycarbonylamino-4,4-dibenzylthiobutanoate (4):
Racemic aldehyde 34a,7 (16.3 g, 47 mmol), benzyl mercaptan (5.5 mL,
47 mmol) and TsOH (0.2 g, 1 mmol) in toluene (110 mL) are refluxed in a
flask fitted with a Dean-Stark apparatus. After 12 h, the reaction mixture is
washed with satd. aq. sodium carbonate then with water. The organic phase
is dried (Na2SO4), filtered and evaporated to leave an oily residue.
Purification by silica gel flash chromatography gives an oil (19 g, 70%).
Crystallization of dithioacetal 4 occurs in Et2O/pentane: mp ¼ 65ꢀC.
1H NMR (200 MHz, CDCl3) : d ¼ 2.10–2.50 (m, 2H, CH2); 3.55 (br t,
1H, J ¼ 7.6 Hz, SCHS); 3.65–3.90 (m, 4H, SCH2); 4.6 (m, 1H, CHN);
5.00–5.30 (m, 5H, NH, OCH2); 7.10–7.50 (m, 20H, Harom.).
13C NMR (50.3 MHz, CDCl3) : d ¼ 34.7; 35.1; 37.8 (CH2, SCH2); 46.5
(SCHS); 52.3 (CHN); 66.9; 67.3 (OCH2); 127.0–137.0 (Carom.); 155.6
(NHCO2Bn); 171.2 (CO2Bn).
MS (DCI, NH3): m/z 589 (M þ NH4)þ, 497 (M-PhCH3 þ NH4)þ, 480
(M-PhCH3 þ H)þ, 465 (M-BnSH þ NH4)þ, 448 (M-BnSH þ H)þ.
Analysis: calcd C33H33NO4S2: C : 69.32; H : 5.82; N : 2.45; found:
C:69.11; H : 5.88; N : 2.51.

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MEFFRE AND DURAND
Benzyl (2RS)-2-Benzyloxycarbonylamino-4-benzylthio-4-benzylsulfinyl-
butanote (5): To a stirred solution of dithioacetal 4 (10 g, 17.6 mmol) in
methanol (140 mL) and dioxanne (70 mL) is added dropwise a solution of
sodium metaperiodate (3.7 g, 17.6 mmol) in water (30 mL) at 0ꢀC. The reac-
tion mixture is left under stirring at r.t. for 20 h. After filtration, the filtrate is
concentrated under reduced pressure and extracted with CH2Cl2. The
organic phase is washed with water, dried (Na2SO4) and evaporated
to leave an oily residue. Purification by silica gel flash chromatography
(pentane/EtOAc ¼ 5/1 then EtOAc) gives sulfoxide 5 (8.5 g, 80%) as a color-
less oil (mixture of diastereoisomers).
1H NMR (200 MHz, CDCl3): d ¼ 1.9–3 (m, 2H, CCH2C); 3.5–4.2 (m,
5H, PhCH2S(O), SCHS(O), PhCH2S), 4.5–4.8 (m, 1H, CHN); 4.9–5.2 (m,
4H, OCH2Ph); 5.3–5.7 (m, 1H, NH); 6.9–7.5 (m, 20H, Harom.).
MS:448 (M-PhCH2SOH þ H)þ; 465 (M-PhCH2SOH þ NH4)þ.
A crystalline material is obtained from Et2O/pentane:mp ¼ 102–
103ꢀC. The following analyses as well as a 2D COSY NMR experiment
suggest the presence of one stereoisomer (pair of enantiomers), the relative
configurations of stereogenic centers have not been determined:
1H NMR (200 MHz, CDCl3): d ¼ 2.10; 2.59 (2m, 2H, CCH2C); 3.62 (d,
1H, J ¼ 12.7 Hz, PhCHS(O)); 3.72 (m, 1H, SCHS(O)); 3.87; 3.98 (2d, 2H,
J ¼ 12.8 Hz, CH2S); 4.17 (d, 1H, J ¼ 12.7 Hz, PhCHS(O)); 4.75 (br t, 1H,
J ¼ 9 Hz, CHN); 5.14; 5.18 (2 br s, 4H, OCH2Ph); 5.30 (br d, 1H, J ¼ 8.9 Hz,
NH); 7.15–7.45 (m, 20H, Harom.).
13C NMR (50.3 MHz, CDCl3): d ¼ 28.7 (CCH2C); 37.2 (SCH2); 51.5
(S(O)CH2); 52.9 (CHN); 59.0 (SCHS(O)); 67.1; 67.5 (OCH2); 136.5–127.6
(Carom.); 156.1 (NHCO2Bn); 171.1 (CO2Bn).
MS (DCI, NH3): m/z 448 (M-PhCH2SOH þ H)þ; 465 (M-
PhCH2SOH þ NH4)þ.
Analysis: calcd C33H33NO5S2: C:67.44; H:5.66; N:2.38; found: C:67.27;
H:5.76; N:2.39.
Benzyl (2RS, 3E )-2-Benzyloxycarbonylamino-4-benzylthio-3-butenoate
(6E ) and Benzyl (2RS, 3Z )-2-Benzyloxycarbonylamino-4-benzylthio-3-
butenoate (6Z ): Sulfoxide 5 (1.4 g, 2.4 mmol, mixture of diastereoisomers)
and calcium carbonate (0.5 g, 5 mmol) in toluene (50 mL) are refluxed for
4 h. After filtration and evaporation of the solvent, the oily residue is pur-
ified by silica gel flash chromatography (Pentane/EtOAc ¼ 5/1).
The following compounds are successively isolated:
6E: 0.34 g (32%), white solid, mp ¼ 55ꢀC
6E/6Z ¼ 1/1 mixture: 0.15 g (14%)
6Z: 0.045 g (4%), white solid, mp ¼ 80ꢀC
Also recovered: 5: 0.4 g (29%).

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293
6E: 1H NMR (200 MHz, CDCl3): d ¼ 3.88 (br s, 2H, CH2S); 4.96 (br t,
1H, J ¼ 7 Hz, CHN); 5.18; 5.24 (2 br s, 4H, CH2O); 5.46 (br d, 1H,
J ¼ 7.5 Hz, NH); 5.56 (dd, 1H, J ¼ 7 Hz, 15.2 Hz, SCH¼CH); 6.37 (d, 1H,
J ¼ 15.2 Hz, SCH¼CH); 7.20–7.50 (m, 15H, Harom.).
13C NMR (50.3 MHz, CDCl3): d ¼ 36.8 (CH2S); 55.9 (CHN); 67.1;
67.4 (CH2O); 120.8 (SC¼C ); 127.3–128.7 (CHarom.); 129.3 (SC¼C); 135.0;
136.0; 136.5 (Carom.); 155.0 (NHCO2Bn); 170.0 (CO2Bn).
MS (DCI, NH3): m/z 448 (M þ H)þ; 465 (M þ NH4)þ.
IR (in fluorolube, cmꢁ1): 3300, 3050, 2950, 1750, 1700, 1540, 1500,
1460, 1375, 1350.
Analysis: calcd C26H25NO4S: C:69.78; H:5.63; N:3.23; found: C:69.32;
H:5.83; N:3.22.
6Z: 1H NMR (200 MHz, CDCl3): d ¼ 3.90 (br s, 2H, CH2S); 5.00–5.30
(m, 5H, CHN þ CH2O); 5.30–5.60 (br t, 2H, J ¼ 9 Hz, SCH¼CH þ NH);
6.30 (d, 1H, J ¼ 9.4 Hz, SCH¼CH); 7.20–7.50 (m, 15H, Harom.).
13C NMR (50.3 MHz, CDCl3): d ¼ 38.1 (CH2S); 53.7 (CHN); 66.9;
67.2 (CH2O); 122.6 (SC¼C ); 127.3–128.8 (CHarom.); 131.3 (SC¼C); 135.2;
136.1; 137.1 (Carom.); 155.0 (NHCO2Bn); 170.0 (CO2Bn).
MS (DCI, NH3): m/z 448 (M þ H)þ; 465 (M þ NH4)þ.
IR (in fluorolube, cmꢁ1): 3350, 3050, 2950, 1750, 1690, 1525, 1500,
1450, 1375, 1325.
Analysis: calcd C26H25NO4S: C:69.75; H:5.63; N:3.23; found: C:69.39;
H:5.81; N:3.04.
When thermolysis of sulfoxide 4 is performed under more drastic
conditions in order to increase the conversion (refluxing xylene or increase
of reaction time in refluxing toluene), conjugation of the double bond
is observed and various proportions of the a,b-unsaturated isomers
are obtained but the isomers are not easily separated by silica gel flash
chromatography.
Methyl (2S, 3E)-2-Phthalimido-4-methylthio-3-butenoate (8E ): The
chlorination step is performed in an amber flask in order to protect the
reaction mixture from light. N-Chlorosuccinimide (1.47 g, 11 mmol) was
added in one portion to a stirred solution of Methyl-(S )-2-Phthalimido-
4-methylthiobutanoate (7) (2.93 g, 10 mmol)11a,b in CCl4 (30 mL) at
room temperature, under an argon atmosphere. After stirring for 3 h, the
supernatant succinimide is filtered, washed with CCl4 and the filtrate
evaporated. DMF(40 mL) is added and the reaction flask (fitted with a
CaCl2 drying tube) is heated to 70ꢀC for 2 h. Satd. aq. NaHCO3 (100 mL)
and EtOAc (100 mL) are added to the reaction mixture. The
aqueous phase is extracted with EtOAc (3 Â 50 mL). The combined organic
phases are washed with water and dried (Na2SO4). After evaporation of the
solvent, silica gel flash chromatography is performed (cyclohexane-EtOAc,

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5 : 1) to give 8 (2.0 g, 69%, (E )/(Z ) ꢂ 6.7/1 by 1H NMR analysis) as a
colorless oil.
Crystallisation of major (E ) isomer resulted in a mixture of hexanes-
Et2O at 0ꢀC. mp ¼ 74–76ꢀC. [a]D20 ¼ þ11 (c ¼ 1.2, CHCl3).
Optical purity of the major (E ) isomer is 90–91% ee based on HPLC
analysis over a 25 cm  0.46 cm Chiracel OJ column using hexane-isopropyl
alcohol (70:30) as eluent and a flow rate of approximately 1 mL minꢁ1. The
peak assignment was confirmed by co-injections of the R-isomer synthesized
by the same method. The S-isomer elutes with a retention time of 38 min
while the R-isomer has a retention time of 52 min.
8E: 1H NMR (200 MHz, CDCl3): d ¼ 2.29 (s, 3H, CH3S), 3.78 (s, 3H,
CO2CH3), 5.46 (d, 1H, J ¼ 8.5 Hz, CHN), 5.87 (dd, 1H, J ¼ 8.5 Hz, 15 Hz,
CH¼CH-CHN), 6.49 (d, 1H, J ¼ 15 Hz, S-CH¼CH), 7.70–7.90 (m,
4H, Pht).
13C NMR (50.3 MHz, CDCl3): d ¼ 14.2 (CH3S), 53.0, 53.7 (CHN,
CO2CH3),115.6(SCH¼CH),123.5(CHarom),131.8(Carom),133.0(SCH¼CH),
134.1 (CHarom), 166.9, 168.6 (CO).
MS (DCI, NH3): m/z 292 (M þ H)þ, 309 (M þ NH4)þ.
IR (KBr, cmꢁ1): 3070, 3040, 2960, 2920, 2900, 1775, 1740, 1735, 1630,
1620, 1470, 1420, 1390.
Analysis: calcd C14H13NO4S: C:57.72; H : 4.50; N : 4.81; found:
C : 57.55; H : 4.56; N : 4.73
1
For comparison and (E)/(Z) ratio determination: H NMR: 8Z: 5.75
(d, J ¼ 8 Hz), 6.14 (dd, J ¼ 8, 9.4 Hz), 6.33 (d, J ¼ 9.4 Hz). 8Z was fully
described previously by us, see ref.13a
ACKNOWLEDGMENTS
We thank Dr N. Sellier (Service de Spectrometrie de Masse de
l’ENSCP) for MS analyses.
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route described here from racemic homoserine was not considered to

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be efficient enough to be transposed to expensive optically active
material.
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Received in the UK December 1, 2000

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