Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations

Article abstract of DOI:10.1002/hlca.201700196

Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester derivatives. Here we present a straightforward synthetic route to MTMs that proceeds through nucleophilic ring-opening of Meldrum's acid derivatives followed by O-alkylation of the resulting malonic acid half thioesters with alkyl triflates or acetimidates as electrophiles. The method affords MTMs in overall yields of 34?–?92% and allows for variations of the oxo- and thioester moieties as well as the substituent at the C(α) position.

Full text of DOI:10.1002/hlca.201700196

Article Type: Full Paper
Synthesis of Monothiomalonates (MTMs) – Versatile Thioester
Enolate Equivalents for C–C Bond Formations
Oliver D. Engl,+ Jakub Saadi,+ Elena Cosimi, and Helma Wennemers*
ETH Zurich, Laboratorium für Organische Chemie, D-CHAB, Vladimir-Prelog-Weg 3, 8093 Zurich
(Switzerland)
e-mail: helma.wennemers@org.chem.ethz.ch
webpage: http://www.wennemers.ethz.ch
Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C
bond formations under mild conditions and thereby afford access to synthetically versatile thioester
derivatives. Here we present a straightforward synthetic route to monothiomalonates (MTMs) that
proceeds through nucleophilic ring-opening of Meldrum’s acid derivatives followed by O-alkylation
of the resulting malonic acid half thioesters (MAHTs) with alkyl triflates or acetimidates as
electrophiles. The method affords MTMs in overall yields of 34–92 % and allows for variations of the
oxo- and thioester moieties as well as the substituent at the Cα position.
Keywords: thioesters • synthesis • organocatalysis • esterification• malonates
Introduction
Thioesters are versatile building blocks in organic synthesis as they can be readily transformed into a
variety of other functional groups such as aldehydes, ketones, esters, and amides.[1-3] In comparison
to related oxoesters, thioesters are ~100 fold more reactive towards common nucleophiles such as
amines or thiolates and therefore attractive acylating reagents.[4-7] The stereoselective introduction
of thioesters into organic molecules is therefore important. Among the most straightforward
methods are C–C bond formations that utilize thioester enolates.[8-57] The formation of thioester
enolates under mild conditions is not trivial due to the comparatively low acidity of the proton at the
α-carbon (Cα) combined with the reactivity of thioesters towards nucleophilic bases.[58]
Organocatalytic methods that use surrogates of thioester enolates have therefore become popular
for the stereoselective incorporation of thioester moieties into organic molecules.[16-26,34-37,39-57]
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In nature, malonic acid half thioesters (MAHTs) serve as thioester enolate surrogates and building
blocks for the synthesis of fatty acids and polyketides.[59,60] MAHTs have also been utilized in organic
synthesis for stereoselective addition reactions.[27–47] However, MAHTs are prone to undergo base-
promoted decarboxylation, without a concomitant C–C bond formation, and their reactivity towards
C–C bond formations is relatively low. As a result, reactions involving MAHTs as nucleophiles
typically require the use of a large amount of catalyst (≥10 mol%) and long reaction times.
Monothiomalonates (MTMs), the protected variants of MAHTs, overcome both drawbacks.[48]
Moreover, MTMs bearing a removable protecting group on the oxoester moiety allow for a
controlled addition reaction and subsequent decarboxylation upon removal of the protecting group.
Organocatalytic addition reactions between MTMs and electrophiles proceed therefore in the
presence of low catalyst loadings (1–5 mol%) and provide the corresponding addition products in
enhanced yields and stereoselectivities compared to reactions with MAHTs.[48–57] The addition
products, among which γ-nitrothioesters,[48-50] β-amino thioesters,[51-53] indoles,[54] dihydrocoumarins
and dihydroquinolinones,[55] and oxindoles,[56,57] contain aside from the thioester orthogonally
addressable functional groups and are therefore valuable synthetic building blocks. The reactivity of
the MTMs depends on the thio- and oxester moieties, which also influence the stereoselectivity of
the addition reactions.[49,50,53,55] Thus, a viable synthetic route to MTMs must tolerate different
substituents at Cα and allow for variations of the oxo- and thioester moieties.
MTMs have so far been prepared by the selective mono-alcoholysis of diphenyl dithiomalonates in
the presence of copper(II) as catalyst[61,62] or stepwise condensation of the malonic acid, first with an
alcohol and then with a thiol.[48,54,59] The latter approach requires the use of coupling reagents and is
not generally applicable, e. g., MTMs with electron poor thioester moieties were only obtained in
poor yields. The Cu(II)-catalyzed desymmetrization affords in our hands malonic acid dioxoesters
(MADOs) as side products that are difficult to remove from the desired MTM. Thus, both routes have
severe drawbacks that limit their applicability and the utilization of MTMs as thioester enolate
surrogates.
Herein we present a synthetic route that converts commercially available Meldrum’s acid derivatives
in two steps via MAHTs into MTMs (Scheme 1). The key step is the O-alkylation of MAHTs under
base-free conditions with acetimidates or alkyl triflates. This methodology provides access to MTM
derivatives with alkyl or aryl substituents on the oxo- and thioester moieties and tolerates different
substituents at the Cα position.
R2
O
O
R2
O
O
SH
S
OH
O
O
R1
R1
MAHT
Meldrum‘s acid
NH
CCl3
R3
R3–OTf
or
O
O
O
R2
R3
S
O
R1
MTM
Scheme 1. Two-step synthesis of MTMs from Meldrum‘s acid derivatives.
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Results and Discussion
Synthesis of Malonic Acid Half Thioesters (MAHTs)
We started our studies by evaluating effective conditions for the synthesis of MAHTs that tolerate
different substituents at Cα and the thioester moiety. Shair and co-workers showed that the
nucleophilic ring-opening of methyl Meldrum’s acid in the presence of thiophenol provides the
corresponding α-methyl substituted MAHT in high yield.[32] We explored the scope of this
methodology for the synthesis of MAHTs. Meldrum’s acid derivatives are commercially available or
were readily prepared from malonic acid derivatives by acetal formation in the presence of acetone
and sulfuric acid as catalyst.[62] The nucleophilic ring-opening of Meldrum’s acid derivatives bearing
alkyl, benzyl, allyl, and fluorine at Cα was then investigated with different aryl thiols under the
reaction conditions previously reported by Shair.[32] Reassuringly, Meldrum’s acid 1a readily reacted
with various electron rich and electron deficient aryl thiols 2a–e in the presence of triethylamine and
trimethylsilyl chloride in almost stoichiometric ratios to afford the corresponding MAHTs 3a–e in
moderate to high yields (43–95%) after 12 h at 45 °C (Scheme 2). These experiments also showed
that the addition of trimethylsilyl chloride is crucial to prevent decarboxylation of the resulting
MAHTs, presumably due to the formation of silyl ester malonates as stabilized intermediates
(Scheme 2).[62-64] Unsubstituted Meldrum’s acid 1b as well as derivatives bearing ethyl, benzyl, and
allyl substituents at Cα (1c–e) also reacted readily and MAHTs 3f–i were obtained in yields of 76–
84%. Notably, reactions with substrates 1c–e required an elevated reaction temperature of 65 °C
and longer reaction times (24 h) to obtain these results. In contrast, α fluoro Meldrum’s acid 1f only
reacted sluggishly under these reaction conditions. However, when performing the nucleophilic ring-
opening of 1f in the presence of TMS-protected p-methoxybenzenethiol, the corresponding
fluorinated MAHT 3j was obtained in a yield of 85%. These studies show that this reaction between
thiols and Meldrum’s acid is robust and tolerates a broad range of different substrates. Noteworthy,
the reaction requires for most examples only an extractive workup to isolate the corresponding
MAHTs in high purity.
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NEt3 (1.1 equiv.)
TMS-Cl (1.1 equiv.)
O
O
O
O
R2
R2
+
O
CH3CN (1.0 M)
45 °C, 12 h
O
S
OH
SH
2a-e (1.05 equiv.)
R1
1a-f
R1
3a-j
via:
O
O
R1 = Me (1a), H (1b),
Et (1c), Bn (1d),
allyl (1e), F (1f)
R2 = 4-OMe (2a), H (2b),
4-CF3 (2c), 2-F (2d),
2,4-Me (2e)
R2
TMS
S
O
R1
MeO
O
O
O
O
O
O
O
O
O
S
OH
S
OH
OH
OH
OH
OH
Me
Me
Me
Me
Me
3a, 95% yield
3b, 95% yield
F3C
O
O
S
S
OH
OH
OH
OH
F
3c, 45% yieldb
3d, 72% yield
Me
MeO
MeO
MeO
O
O
S
O
O
O
S
Me
H
3e, 43% yielda,b
3f, 76 % yield
MeO
MeO
O
S
O
S
Et
Bn
3g, 80% yielda,b
3h, 84% yielda
O
S
O
S
F
3i, 79% yielda,b
3j, 85% yieldc
Scheme 2. Synthesis of MAHTs 3a–j. Reactions were performed on a 1.26–12.62 mmol scale. aReaction temperature 65 °C, reaction time 24 h. bAfter flash
column chromatography. cReaction was performed with TMS-protected p-methoxybenzenethiol (1.2 equiv.) in CHCl2CHCl2 at 80 °C for 5 h.
Esterification of Malonic Acid Half Thioesters (MAHTs)
Next, we explored the conversion of MAHTs into MTMs. This esterification of the carboxylic acid is
not trivial since MAHTs are prone to decarboxylation. For example, even weak bases such as tertiary
amines promote the decarboxylation of MAHTs as shown by Brunner.[62] We chose the formation of
a p-methoxybenzyl (PMB) ester to develop the reaction conditions for the esterification since it is a
versatile protecting group for carboxylic acids that can be easily removed under acidic conditions.[48–
57]
In light of the work by Brunner, it was not surprising that treatment of MAHT 3a with alkyl chlorides
or bromides in the presence of a base (e.g. NEt3) led only to the formation of the corresponding
thiopropionate. The reaction of MAHT 3a with p-methoxybenzyl alcohol in the presence of coupling
reagents (e.g., DCC or EDC) afforded MTM 4a but in low yields (≤10 %) along with significant
amounts of side products, such as the corresponding malonate and thiopropionate. These results
show that the synthesis of MTMs from MAHTs requires non-basic conditions. We therefore turned
our attention to 2,2,2-trichloroacetimidates as reagents, which do not require the addition of base
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for the esterification of carboxylic acids.[65-67] Instead, the reaction is promoted through the
protonation of the acetimidate moiety by the carboxylic acid itself and affords 2,2,2-
trichloroacetamide as the only byproduct. After testing different reaction conditions with respect to
solvent, stoichiometry, etc. we found that the treatment of MAHT 3a with a slight excess of
p-methoxybenzyl-2,2,2-trichloroacetimidate (1.2 equiv.) at room temperature afforded the
corresponding PMB-protected MTM 4a in 91% yield (Scheme 3). Other MAHTs with variations at Cα
and the thioester moiety also reacted readily under these conditions and MTMs 4b–j were isolated
in yields greater than 80%.
1.2 equiv. NH
O
O
O
O
PMB
R2
R2
O
CCl3
PMB
S
OH
S
O
CH2Cl2 (0.5 M)
rt, 24 h
R1
3a–3j
R1
4a–4j
MeO
O
O
O
O
PMB
PMB
S
O
S
O
Me
Me
4a, 91% yield
4b, 83% yield
F3C
O
S
O
O
O
PMB
PMB
O
S
O
Me
F
Me
4c, 85% yield
4d, 84% yield
Me
MeO
O
S
O
O
S
O
PMB
PMB
O
O
Me
Me
H
4e, 80% yield
4f, 93% yield
MeO
MeO
MeO
O
S
O
O
O
S
O
PMB
PMB
PMB
PMB
O
O
O
O
Et
Bn
4g, 85% yielda
4h, 93% yielda
MeO
O
S
O
S
O
F
4i, 86% yielda
4j, 94% yield
Scheme 3. Synthesis of MTMs 4a–4j. Reactions were performed on a 0.18–4.16 mmol scale. aReaction was performed with 1.5 equiv. of p-methoxybenzyl-
2,2,2-trichloroacetimidate.
We continued to examine the scope of this reaction by using different 2,2,2-trichloroacetimidate
reagents and reacted Cα methyl and fluorine substituted MAHTs 3a and 3j with methyl, ethyl,
benzyl, allyl, and tert-butyl derivatives.
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1.2 equiv. NH
O
O
O
O
R3
PMP
PMP
R3
O
CCl3
S
OH
S
O
R1
R1 = Me (3a) or F (3j)
R1
CH2Cl2 (0.5 M)
rt, 24 h
4k–4n
O
O
O
O
PMP
PMP
tBu
PMP
PMP
S
O
S
O
Me
4k, 94% yield
F
4l, 65% yield
O
O
O
O
Bn
tBu
S
O
S
O
F
F
4m, 50% yield
4n, 77% yielda
Scheme 4. Synthesis of MTMs 4k–4n using 2,2,2-trichloroacetimidates as electrophiles. Reactions were performed on a 0.18–1.82 mmol scale. aReaction was
performed with 2 equivalents of the 2,2,2-trichloroacetimidate. (PMP = p-methoxyphenyl).
The fluorine-substitued MAHT 3j reacted with the allyl, benzyl, and tert-butyl
2,2,2-trichloroacetimidates and provided the desired MTMs 4l–n in moderate to good yields (50–
77%) while the reaction with the methyl and ethyl 2,2,2-trichloroacetimidates did not proceed
(Scheme 4). In case of methyl-substituted MAHT 3a only the reaction with
tert-butyl-2,2,2-trichloroacetimidate afforded MTM 4k in a yield of 94%, whereas the reactions with
all other trichloroacetimidates did not proceed. This suggests that the higher acidity of fluorinated
MAHTs compared to non-fluorinated MAHTs is responsible for the more effective activation of the
2,2,2-trichloroacetimidates towards O-alkylation. We therefore attempted to promote the reaction
with less reactive MAHTs by the addition of Brønsted or Lewis acids like TfOH, BF3, or Mg(OTf)2.
However, also the presence of these acidic additives did not lead to the desired products. We
reasoned that a fast O-alkylation could outcompete the undesired base-promoted decarboxylation
and therefore explored other alkylating reagents. We sought out alkyl trifluoromethanesulfonates
(commonly known as triflates) as reagents with enhanced electrophilicity, which would be
complimentary to trichloroacetimidates for the esterification.[68,69] Several triflates are commercially
available, and many more can be easily prepared from common alcohols and triflic anhydride at −78
°C. Triflates are such strong alkylating reagents that they readily alkylate the nitrogen of most amine
bases and therefore require the use of sterically hindered and non-nucleophilic bases to scavenge
the triflic acid formed in alkylation reactions.[68,69] Indeed, the treatment of MAHTs 3a and 3j with
commercially available methyl and ethyl triflates at –78 °C in the presence of 2,4,5-trimethyl pyridine
as base afforded the corresponding O-alkylated MTMs 5a and 5b as well as 5d and 5e in good to
excellent yields (81–96%) (Scheme 5). Also the reaction of MAHT 3a with benzyl triflate, prepared in
situ from benzyl alcohol, was effective and provided MTM 5c in 93% yield.
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Scheme 5. Synthesis of MTMs 5a–5e using alkyl triflates as electrophiles. Reactions were performed on a 0.12–15.39 mmol scale. (PMP = p-methoxyphenyl)
Conclusions
In summary, we have developed a straightforward synthetic route to MTMs that relies on O-
alkylation of readily accessible MAHTs using alkyl triflates or acetimidates as electrophiles. The
method provides access to MTMs in good to excellent yields starting from Meldrum‘s acid
derivatives and is general for MTMs bearing different substituents on the oxo- and thioester
moieties (including alkyl and aryl groups) as well as at Cα. We envision that our results will enhance
the use of MTMs as surrogates of thioester enolates and thereby enable the synthesis of complex
molecular frameworks.
Experimental Section
General Aspects and Materials
Reactions requiring anhydrous conditions were performed under dry nitrogen or argon atmospheres
in glassware that was dried using a combination of vacuum and heat-gun or oven. Reaction mixtures
were stirred magnetically. Air- and moisture-sensitive liquids and solutions were transferred via
syringe or cannula into the reaction vessels through rubber septa. All reagents and solvents were
purchased at the highest commercial quality available and used as received. Anhydrous solvents
were obtained from a purification column composed of activated alumina (A-2). Yields refer to
spectroscopically pure compounds unless otherwise stated. Flash chromatography was performed
on silica gel (Merck Kieselgel 60 F254 230-400 mesh). TLC was performed on aluminum-backed silica
plates (0.2 mm, 60 F254), which were developed using standard visualizing agents: UV (254 and 366
nm), iodine, ninhydrine / ∆, phosphomolybdic acid / ∆, anisaldehyde / ∆, potassium permanganate /
∆. IR: Recorded on neat compounds using an Agilent Technologies Cary 630 FTIR. Only selected
1
13
19
peaks are shown. NMR: H, C and F NMR spectra were recorded on a Varian Mercury-VX 300, a
Bruker AV 300 (300 MHz/75 MHz), a Bruker DRX 400, a Bruker AV III 400 (400 MHz/100 MHz) or a
1
Bruker AV III 600 (600 MHz/150 MHz). H-NMR: Spectra were recorded on 300, 400, 500, or 600
MHz instruments. Chemical shifts (δH) are quoted in parts per million (ppm) and referenced to the
appropriate solvent peak(s). 13C-NMR: Spectra were recorded on 101, 125, or 150 MHz instruments.
Chemical shifts (δc) are quoted in ppm, referenced to the appropriate solvent peak(s) and are
assigned C, CH, CH2 and CH3. COSY, HSQC, 15N-HSQC and HMBC were used where necessary for
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19
assigning NMR spectra. F-NMR: Chemical shifts (δF) are quoted in parts per million (ppm) and are
not referenced. HRMS: high resolution mass spectra were recorded on a Bruker maXis (UHR-TOF) for
high-resolution electrospray ionisation (HR-ESI) mass spectrometry, on a Bruker solariX 94
(ESI/MALDI-FT-ICR) and a Bruker Ultra-Flex II (MALDI-TOF) spectrometer for high-resolution MALDI
spectra or an EI-Sector-MS. Commercially available 2,2,5-trimethyl-1,3-dioxane-4,6-dione 1a and
2,2-dimethyl-1,3-dioxane-4,6-dione 1b were either recrystallized (CH2Cl2/methanol, 9:1) or purified
by flash column chromatography (n-hexane/ethyl acetate, 10:1 to 1:1) prior to their use in the
synthesis.
5-Fluoro-2,2-dimethyl-1,3-dioxane-4,6-dione
1f
and
((4-methoxyphenyl)thio)trimethylsilane were synthesized following previously published procedures
and characterized by comparison of at least two pieces of spectral data with those reported in the
literature.[49]
General method for the synthesis of Meldrum’s acids
To a suspension of the malonic acid (1.0 equiv.) in acetic anhydride (6.0 M) was added concentrated
sulfuric acid (0.005 mL/mmol). Acetone (0.1 mL/mmol) was then added dropwise to the suspension
at 0 °C and the resulting solution was stirred at room temperature for 16 h. The formed solid was
filtered and washed with ice water to afford the desired product. In the cases where no solid
formed, the reaction mixture was poured into water (2.0 mL/mmol) and extracted with diethyl ether
(3 × 2.0 mL/mmol). The organic layers were combined and extracted with sat. aq. NaHCO3 (3 ×
2.0 mL/mmol). 6 M HCl was slowly added at 0 °C to the aqueous solution until the pH was 2–3. The
aqueous solution was extracted with diethyl ether (3 × 4.0 mL/mmol), the organic layer was washed
with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the product.
General method for the synthesis of MAHTs
To a solution of Meldrum’s acid (1.0 equiv.) in dry CH3CN (1.0 M) at 0 °C, NEt3 (1.1 equiv.) was added
dropwise followed by trimethylsilylchloride (1.1 equiv.). The reaction mixture was stirred at 0 °C for
5 min and thiol (1.05 equiv.) was added. The reaction mixture was heated to 45–65 °C for 12–24 h.
The reaction mixture was cooled to room temperature and 0.5 M HClaq (8 mL/mmol) was added. The
organic layer was separated and the aqueous layer was extracted with Et2O (3 × 10 mL/mmol). The
organic layers were combined and extracted with sat. aq. NaHCO3 solution (10 mL/mmol). 4 M HClaq
was slowly added to the aqueous layer at 0 °C with vigorous stirring until the pH was 2–3. The
solution became cloudy and white as the pH fell below 5. The aqueous layer was extracted with Et2O
(3 × 10 mL/mmol), dried over Na2SO4, and concentrated under reduced pressure to afford the
product as a white solid. If necessary the product was purified by flash column chromatography
(CH2Cl2/MeOH, 10:0 to 9:1).
General method A for the synthesis of MTMs
The malonic acid half thioester (1.0 equiv.) was dissolved in dry CH2Cl2 (0.5 M) and cooled to 0 °C.
Then, the alkyl 2,2,2-trichloroacetimidate derivative (1.2–1.5 equiv.) was added and the reaction
mixture was stirred for 18 h at room temperature. The reaction mixture was washed with 5%
NaHCO3 aq. (3 mL/mmol), extracted with CH2Cl2 and the combined organic phases were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude mixture was purified
by flash chromatography on silica, eluting with EtOAc/n-hexane.
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General method B for the synthesis of MTMs
The malonic acid half thioester (1.0 equiv.) was dissolved in CH2Cl2 (0.5 M), cooled to –78 °C and
2,4,6-trimethyl pyridine (1.3 equiv.) was added dropwise. The reaction mixture was stirred for 5 min
before the alkyl triflate (1.2 equiv.) was added dropwise. The reaction mixture was stirred for 16 h
and allowed to warm up to room temperature. To the reaction mixture was added 5% NaHCO3 (1.8
mL/mmol) and it was then extracted with CH2Cl2 (3 × 2.0 mL/mmol). The combined organic phases
were washed with 1N HCl (1.8 mL/mmol) and brine (1.8 mL/mmol), dried over Na2CO3, filtered and
concentrated under reduced pressure. The resulting crude mixture was purified by flash
chromatography on silica, eluting with EtOAc/n-hexane.
Synthesis of Meldrum’s acids 1c−e
5-Ethyl-2,2-dimethyl-1,3-dioxane-4,6-dione (1c). According to the general method on a 30.28 mmol
scale, the product was obtained as a white solid (4.00 g, 77% yield). Analytical data: FT-IR (neat):
1
3
2888 (C-H aliph.), 1773 (br, C=O). H-NMR (300 MHz, CDCl3, 298 K): 3.52 (1 H, t, JHH = 5.0 Hz,
CHCH2CH3), 2.31-1.99 (2 H, m, CHCH2CH3), 1.79 (3 H, s, CH3), 1.76 (3 H, s, CH3), 1.05 (3 H, t, 3JHH = 7.0
Hz, CHCH2CH3). 13C-NMR (100 MHz, CDCl3, 298 K): 165.5 (C=O), 164.8 (C), 47.1 (CH), 28.4 (CH3), 26.9
(CH3). HR-MALDI-MS (pos.): 195.0628 ([M + Na]+, C8H12O4Na+; calc. 195.0628).
5-Benzyl-2,2-dimethyl-1,3-dioxane-4,6-dione (1d). According to the general method on a 10.30
mmol scale, the product was obtained as a white solid (1.50 g, 62% yield). Analytical data: FT-IR
1
(neat): 2999 (C-H arom. and C-H aliph.), 1741 (br, C=O). H-NMR (300 MHz, CDCl3, 298 K): 7.38-7.21
(5 H, m, ArH), 3.79 (1 H, t, 3JHH = 5.0 Hz, CHCH2Ph), 3.51 (2 H, d, 3JHH = 5.0 Hz, CHCH2Ph), 1.75 (3 H, s,
CH3), 1.51 (3 H, s, CH3). 13C-NMR (100 MHz, CDCl3, 298 K): 165.3 (C=O), 137.3 (Ar), 129.8 (ArH), 128.6
(ArH), 127.2 (ArH), 105.3 (C), 48.2 (CH), 28.5 (CH3), 27.2 (CH3). HR-MALDI-MS (pos.): 257.0784 ([M +
Na]+, C13H14O4Na+; calc. 257.0784).
5-Allyl-2,2-dimethyl-1,3-dioxane-4,6-dione (1e). According to the general method on a 27.70 mmol
scale, the product was obtained as a white solid (3.00 g, 59% yield). Analytical data: FT-IR (neat):
1
3
2886 (C-H aliph.), 1774 (C=O), 1735 (C=O). H-NMR (300 MHz, CDCl3, 298 K): 5.86 (1 H, ddt, JHH =
17.0 Hz, 3JHH = 10.0 Hz, 3JHH = 7.0 Hz, CHCH2CHCH2), 5.37-5.07 (2 H, m, CHCH2CHCH2), 3.61 (1 H, t, 3JHH
= 5.0 Hz, CHCH2CHCH2), 2.91-2.86 (2 H, m, CHCH2CHCH2), 1.80 (3 H, s, CH3). 13C-NMR (100 MHz,
CDCl3, 298 K): 165.0 (C=O), 132.6 (CH), 119.4 (CH2), 105.0 (C), 46.2 (CH), 30.3 (CH2), 28.4 (CH3), 27.0
(CH3). HR-MALDI-MS (pos.): 207.0628 ([M + Na]+, C9H12O4Na+; calc. 207.0628).
Synthesis of MAHTs 3a-j
3-((4-Methoxyphenyl)thio)-2-methyl-3-oxopropanoic acid (3a). According to the general method on
a 12.62 mmol scale at 45 °C for 12 h, the product was obtained as a white solid (2.88 g, 95% yield).
Analytical data: FT-IR (neat): 3093 (br, CO2H), 2940 (br, C-H arom. and C-H aliph.), 1719 (C=O), 1697
(C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 9.75 (1 H, br s, COOH), 7.42-732 (2 H, m, ArH), 7.01-6.91 (2
H, m, ArH), 3.85 (3 H, s, OCH3), 3.81 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 1.54 (3 H, q, 3JHH = 7.0 Hz, CHCH3).
13C-NMR (100 MHz, CDCl3, 298 K): 195.0 (C=O), 174.4 (C=O), 161.0 (Ar), 136.1 (ArH), 117.3 (Ar), 115.0
(ArH), 55.4 (OCH3), 53.0 (CH), 14.2 (CH3). HR-ESI-MS (pos.): 263.0352 ([M + Na]+, C11H12O4SNa+; calc.
263.0349). Anal. calc. for C11H12O4S: C 54.99, H 5.03, O 26.63; found: C 54.73, H 5.06, O 26.86.
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2-Methyl-3-oxo-3-(phenylthio)propanoic acid (3b). According to the general method on a 1.26
mmol scale at 45 °C for 12 h, the product was obtained as a white solid (251 mg, 95% yield).
Analytical data: FT-IR (neat): 3059 (br, COOH), 2939 (br, C-H arom. and C-H aliph.), 1695 (br, C=O).
1H-NMR (300 MHz, CDCl3, 298 K): 10.11 (1 H, br s, COOH), 7.58-7.31 (5 H, m, ArH), 3.83 (1 H, q, 3JHH
7.0 Hz, CHCH3), 1.56 (3 H, d, JHH = 7.0 Hz, CHCH3). C-NMR (100 MHz, CDCl3, 298 K): 193.9 (C=O),
174.8 (C=O), 134.5 (ArH), 129.9 (ArH), 129.4 (ArH), 126.6 (Ar), 53.3 (CH), 14.2 (CH3). HR-ESI-MS
(pos.): 233.0245 ([M + Na]+, C10H10O3SNa+; calc. 233.0243).
=
3
13
2-Methyl-3-oxo-3-((4-(trifluoromethyl)phenyl)thio)propanoic acid (3c). According to the general
method on a 1.26 mmol scale at 45 °C for 12 h, the product was obtained as a white solid (157 mg,
45% yield). Analytical data: FT-IR (neat): 2990 (br, COOH), 2839 (br, C-H arom. and C-H aliph.), 1708
1
(C=O), 1683 (C=O). H-NMR (300 MHz, CDCl3, 298 K): 10.26 (1 H, br s, COOH), 7.75 (2 H, m, ArH),
3
3
13
7.64-7.47 (2 H, m, ArH), 3.85 (1 H, q, JHH = 7.0 Hz, CHCH3), 1.58 (1 H, d, JHH = 7.0 Hz, CHCH3). C-
2
NMR (100 MHz, CDCl3, 298 K): 192.5 (C=O), 174.7 (C=O), 134.6 (Ar), 131.8 (q, JHF = 33.0 Hz, Ar),
131.2 (q, 4JHF = 2.0 Hz, ArH), 126.1 (q, 3JHF = 4.0 Hz, ArH), 123.7 (q, 1JHF = 272.5 Hz, CF3), 53.6 (CH), 14.1
(CH3). 19F-NMR (377 MHz, CDCl3, 298 K): −63.0 (br s). HR-ESI-MS (pos.): 301.0124 ([M + Na]+,
C11H9F3O3SNa+; calc. 301.0117).
3-((2-Fluorophenyl)thio)-2-methyl-3-oxopropanoic acid (3d). According to the general method on a
1.94 mmol scale at 45 °C for 12 h, the product was obtained as a white solid (320 mg, 72% yield).
Analytical data: FT-IR (neat): 2990 (br, COOH), 2882 (br, C-H arom. and C-H aliph.), 1699 (br, C=O).
1H-NMR (300 MHz, CDCl3, 298 K): 10.51 (1 H, br s, COOH), 7.53-7.40 (2 H, m, ArH), 7.26-7.14 (2 H, m,
ArH), 3.86 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 1.58 (1 H, d, 3JHH = 7.0 Hz, CHCH3). 13C-NMR (100 MHz, CDCl3,
298 K): 192.0 (C=O), 174.6 (C=O), 162.1 (d, 1JHF = 250.0 Hz, ArF), 136.6 (ArH), 132.6 (d, 3JHF = 8.0 Hz,
ArH), 124.8 (d, 4JHF = 4.0 Hz, ArH), 116.4 (d, 2JHF = 22.5 Hz, ArH), 114.1 (d, 2JHF = 18.5 Hz, Ar), 53.3 (CH),
14.2 (CH3). 19F-NMR (377 MHz, CDCl3, 298 K): −106.3 (m). HR-ESI-MS (pos.): 229.0335 ([M + H]+,
C10H11FO3S+; calc. 229.0329).
3-((2,4-Dimethylphenyl)thio)-2-methyl-3-oxopropanoic acid (3e). According to the general method
on a 1.26 mmol scale at 65 °C for 24 h, the product was obtained as a white solid (120 mg, 43%
yield). Analytical data: FT-IR (neat): 2995 (br, COOH), 2826 (br, C-H arom. and C-H aliph.), 1716
1
(C=O), 1670 (C=O). H-NMR (300 MHz, CDCl3, 298 K): 9.91 (1 H, br s, COOH), 7.31 (1 H, d, 3JHH = 8.0
Hz, ArH), 7.21-7.13 (1 H, m, ArH), 7.12-7.01 (1 H, m, ArH), 3.84 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 2.36 (3
H, s, ArCH3), 2.33 (3 H, s, ArCH3), 1.56 (3 H, d, 3JHH = 7.0 Hz, CHCH3). 13C-NMR (100 MHz, CDCl3, 298 K):
194.0 (C=O), 174.9 (C=O), 142.0 (Ar), 140.9 (Ar), 135.8 (ArH), 131.8 (ArH), 127.6 (ArH), 122.6 (Ar),
53.1 (CH), 21.3 (ArCH3), 20.5 (ArCH3), 14.2 (CH3). HR-ESI-MS (pos.): 261.0555 ([M + Na]+,
C12H14O3SNa+; calc. 261.0556).
3-((4-Methoxyphenyl)thio)-3-oxopropanoic acid (3f). According to the general method on a 1.26
mmol scale at 45 °C for 12 h, the product was obtained as a yellow oil (202 mg, 76% yield). Analytical
1
data: FT-IR (neat): 2994 (br, COOH), 2837 (br, C-H arom. and C-H aliph.), 1697 (br, C=O). H-NMR
(300 MHz, CDCl3, 298 K): 10.14 (1 H, br s, COOH), 7.42-7.30 (2 H, m, ArH), 7.04-6.90 (2 H, m, ArH),
13
3.85 (3 H, s, OCH3), 3.72 (2 H, s, CH2). C-NMR (100 MHz, CDCl3, 298 K): 191.0 (C=O), 171.2 (C=O),
161.1 (Ar), 136.2 (ArH), 117.1 (Ar), 115.1 (ArH), 55.4 (OCH3), 48.1 (CH2). HR-ESI-MS (pos.): 249.0198
([M + Na]+, C10H10O4SNa+; calc. 249.0192).
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2-(((4-Methoxyphenyl)thio)carbonyl)butanoic acid (3g). According to the general method on a 1.26
mmol scale at 65 °C for 24 h, the product was obtained as a white solid (255 mg, 80% yield).
Analytical data: FT-IR (neat): 2963 (br, COOH), 2839 (br, C-H arom. and C-H aliph.), 1703 (C=O), 1682
(C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 10.7 (1 H, br s, COOH), 7.45-7.30 (2 H, m, ArH), 7.05-6.86 (2
3
H, m, ArH), 3.84 (3 H, s, OCH3), 3.65 (1 H, t, JHH = 7.5 Hz, CHCH3CH3), 2.10-2.01 (2 H, m CHCH2CH3),
3
13
1.07 (3 H, t, JHH = 7.5 Hz, CHCH2CH3). C-NMR (100 MHz, CDCl3, 298 K): 194.3 (C=O), 174.2 (C=O),
160.1 (Ar), 136.1 (ArH), 117.4 (Ar), 115.0 (ArH), 60.4 (CH), 55.4 (OCH3), 23.2 (CH2), 11.8 (CH3). HR-
MALDI-MS (pos.): 277.0505 ([M + Na]+, C12H14O4SNa+; calc. 277.0505).
2-Benzyl-3-((4-methoxyphenyl)thio)-3-oxopropanoic acid (3h). According to the general method on
a 1.26 mmol scale at 65 °C for 24 h, the product was obtained as colorless oil (333 mg, 84% yield).
Analytical data: FT-IR (neat): 3062 (br, COOH), 2939 (br, C-H arom. and C-H aliph.), 1718 (C=O). 1698
(C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 9.83 (1 H, br s, COOH), 7.41-7.18 (7 H, m, ArH), 7.03-6.80 (2
H, m, ArH), 4.02 (1 H, t, 3JHH = 7.5 Hz, CHCH2), 3.84 (3 H, s, OCH3), 3.30 (3 H, d, 3JHH = 7.5 Hz, CHCH2).
13C-NMR (100 MHz, CDCl3, 298 K): 193.8 (C=O), 172.5 (C=O), 160.9 (Ar), 136.9 (Ar), 136.0 (ArH), 129.0
(ArH), 128.6 (ArH), 127.0 (ArH), 117.1 (Ar), 114.9 (ArH), 60.2 (CH), 55.3 (OCH3), 35.4 (CH2). HR-ESI-MS
(pos.): 339.0666 ([M + Na]+, C17H16O4SNa+; calc. 339.0662).
2-(((4-Methoxyphenyl)thiocarbonyl)pent-4-enoic acid (3i). According to the general method on a
1.26 mmol scale at 65 °C for 24 h, the product was obtained as colorless oil (265 mg, 79% yield).
Analytical data: FT-IR (neat): 3078 (br, COOH), 2930 (br, C-H arom. and C-H aliph.), 1736 (C=O). 1700
(C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 10.12 (1 H, br s, COOH), 7.42-7.29 (2 H, m, ArH), 7.03-6.90
3
3
3
(2 H, m, ArH), 5.82 (1 H, ddt, JHH =17.0, JHH = 10.0, JHH = 7.0 Hz, CHCH2CHCH2), 5.28-5.10 (2 H, m,
3
CHCH2CHCH2), 3.84 (3 H, s, OCH3), 3.81 (1 H, t, JHH =7.5 Hz, CHCH2CHCH2), 2.80-2.67 (2 H, m,
CHCH2CHCH2). C-NMR (100 MHz, CDCl3, 298 K): 193.5 (C=O), 173.7 (C=O), 161.0 (Ar), 136.1 (ArH),
13
133.1 (CH), 118.5 (CH2), 117.2 (Ar), 115.0 (ArH), 58.4 (CH), 55.4 (OCH3), 33.5 (CH2). HR-ESI-MS (pos.):
289.0505 ([M + Na]+, C13H14O4SNa+; calc. 289.0505).
2-fluoro-3-((4-methoxyphenyl)thio)-3-oxopropanoic acid (3j). 5-Fluoro-2,2-dimethyl-1,3-dioxane-
4,6-dione (1 equiv., e.g. 1.75 g, 10.8 mmol) and ((4-methoxyphenyl)thio)-trimethylsilane (1.2 equiv.,
e.g. 2.75 g, 12.9 mmol,) were dissolved in dry tetrachloroethane (1 M) under an argon atmosphere.
The mixture was stirred at 80 °C for 5 h. After cooling down to room temperature, the mixture was
diluted with CH2Cl2 (8 mL/mmol), saturated NaHCO3 aq. (1 mL/mmol) and water (1 mL/mmol) and
thoroughly shaken until the evolution of gas stopped. The aqueous layer was extracted with CH2Cl2
(3 x 5 mL/mmol), then acidified with cold 1N HCl (8 mL/mmol) to pH 2-3 and extracted with CH2Cl2 (3
x 5 mL/mmol). The organic layers were dried over Na2SO4, filtered, and concentrated under reduced
pressure to afford the product as a white solid (2.24 g, 85% yield). Analytical data: FT-IR (neat): 3525
(br, COOH), 2945 (br, C-H arom. and C-H aliph.), 1750 (C=O). 1701 (C=O). 1H-NMR (400 MHz, CDCl3,
2
298 K): 8.58 (1 H, br s, COOH), 7.39-7.29 (2 H, m, ArH), 7.02-6.93 (2 H, m, ArH), 5.46 (1 H, d, JHF
=
13
2
48.0 Hz, CHF), 3.84 (3 H, s, OCH3). C-NMR (100 MHz, CDCl3, 298 K): 191.9 (d, JCF = 28.0 Hz, C=O),
167.1 (d, 2JHF = 24.0 Hz, C=O), 161.5 (Ar), 136.5 (ArH), 115.5 (ArH), 114.9 (d, 4JCF = 5.0 Hz, Ar), 90.4 (d,
1JCF = 203.0 Hz, CF), 55.6 (OCH3). F-NMR (377 MHz, CDCl3, 298 K): –192.7 (d, 2JHF = 48.0 Hz). HR-EI-
19
MS (pos.): 244.0205 ([M]+, C10H9FO4S+; calc. 244.0200). Anal. calc. for C10H9FO4S: C 49.18, H 3.71, O
26.2, F 7.78, S 13.13; found: C 49.3, H 3.82, O 26.2, F 7.9, S 13.17.
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Synthesis of MTMs 4a-n
4-Methoxybenzyl 3-((4-methoxyphenyl)thio)-2-methyl-3-oxopropanoate (4a). According to the
general method A on a 4.16 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.2
equiv.), the product was obtained as a colorless oil (1.35 mg, 90% yield). Analytical data: FT-IR
1
(neat): 2938 (br, C-H arom. and C-H aliph.), 1736 (C=O). 1696 (C=O). H-NMR (300 MHz, CDCl3, 298
K): 7.37-7.24 (4 H, m, ArH), 7.00-6.87 (4 H, m, ArH), 5.16 (2 H, s, ArCH2), 3.84 (3 H, s, OCH3), 3.83 (3 H,
3
3
13
s, OCH3), 3.78 (1 H, q, JHH = 7.0 Hz, CHCH3), 1.51 (3 H, q, JHH = 7.0 Hz, CHCH3). C-NMR (100 MHz,
CDCl3, 298 K): 194.9 (C=O), 169.2 (C=O), 160.9 (Ar), 159.7 (Ar), 136.2 (ArH), 130.1 (ArH), 127.5 (Ar),
117.5 (Ar), 114.9 (ArH), 114.0 (ArH), 67.2 (CH2), 55.4 (OCH3), 55.3 (OCH3), 53.5 (CH), 14.1 (CH3). HR-
MALDI-MS (pos.): 383.0924 ([M + Na]+, C19H20O5SNa+; calc. 383.0924). Anal. calc. for C19H20O5S: C
63.32, H 5.59, O 22.19; found: C 63.15, H 5.63, O 22.48.
4-Methoxybenzyl 2-methyl-3-oxo-3-(phenylthio)propanoate (4b). According to the general method
A on a 0.73 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.2 equiv.), the product
was obtained as a colorless oil (200 mg, 83% yield). Analytical data: FT-IR (neat): 2937 (br, C-H arom.
1
and C-H aliph.), 1736 (C=O). 1686 (C=O). H-NMR (300 MHz, CDCl3, 298 K): 7.46-7.36 (5 H, m, ArH),
7.36-7.30 (2 H, m, ArH), 6.96-6.87 (2 H, m, ArH), 5.17 (2 H, s, ArCH2), 3.83 (3 H, s, OCH3), 3.80 (1 H, q,
3
3JHH = 7.0 Hz, CHCH3), 1.53 (3 H, q, JHH = 7.0 Hz, CHCH3). 13C-NMR (100 MHz, CDCl3, 298 K): 193.9
(C=O), 169.1 (C=O), 150.8 (Ar), 134.5 (ArH), 130.1 (ArH), 129.7 (ArH), 129.3 (ArH), 127.5 (Ar), 126.9
(Ar), 114.0 (ArH), 67.3 (CH2), 55.3 (OCH3), 53.8 (CH3), 14.1 (CH3). HR-MALDI-MS (pos.): 353.0817
([M + Na]+, C18H18O4SNa+; calc. 353.0818). Anal. calc. for C18H18O4S: C 65.44, H 5.49, O 19.37; found: C
65.51, H 5.54, O 19.56.
4-Methoxybenzyl 2-methyl-3-oxo-3-((4-(trifluoromethyl)phenyl) thio)propanoate (4c). According to
general method A on a 0.50 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.2
equiv.), the product was obtained as a colorless oil (170 mg, 85% yield). Analytical data: FT-IR (neat):
2940 (br, C-H arom. and C-H aliph.), 1738 (C=O). 1702 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.74-
7.62 (2 H, m, ArH), 7.56-7.45 (2 H, m, ArH), 7.37-7.29 (2 H, m, ArH), 6.96-6.87 (2 H, m, ArH), 5.18 (2
H, s, ArCH2), 3.83 (3 H, s, OCH3), 3.80 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 1.54 (3 H, d, 3JHH = 7.0 Hz, CHCH3).
2
13C-NMR (100 MHz, CDCl3, 298 K): 192.7 (C=O), 168.8 (C=O), 159.8 (Ar), 134.6 (Ar), 131.6 (q, JCF =
32.5 Hz, Ar), 131.6 (q, 4JCF = 2.0 Hz, Ar), 127.8 (Ar), 126.0 (q, 3JCF = 4.0 Hz, ArH), 123.7 (q, 1JCF = 272.7
Hz, ArF), 114.0 (ArH), 67.4 (CH2), 55.3 (OCH3), 54.0 (CH), 14.0 (CH3). 19F-NMR (377 MHz, CDCl3, 298 K):
−63.0 (br s). HR-MALDI-MS (pos.): 421.0691 ([M + Na]+, C19H17F3O4SNa+; calc. 421.0692). Anal. calc.
for C19H17F3O4S: C 57.28, H 4.30; found: C 57.13, H 4.37.
4-Methoxybenzyl 3-((2-fluorophenyl)thio)-2-methyl-3-oxopropanoate (4d). According to general
method A on a 0.87 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.2 equiv.) , the
product was obtained as a colorless oil (254 mg, 84% yield). Analytical data: FT-IR (neat): 2936 (br,
C-H arom. and C-H aliph.), 1737 (C=O). 1703 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.56-7.29 (4 H,
m, ArH), 7.24-7.14 (2 H, m, ArH), 6.99-6.86 (2 H, m, ArH), 5.19 (1 H, d, 2JHH = 12.5 Hz, ArCHH), 5.15 (1
H, d, 2JHH = 12.5 Hz, ArCHH), 3.83 (3 H, s, OCH3), 3.82 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 1.54 (3 H, d, 3JHH
=
7.0 Hz, CHCH3). 13C-NMR (100 MHz, CDCl3, 298 K): 192.1 (C=O), 168.9 (C=O), 162.1 (d, 1JCF =250.5 Hz,
ArF), 159.8 (Ar), 136.6 (ArH), 132.4 (d, 3JCF = 8.0 Hz, ArH), 130.1 (ArH), 127.4 (Ar), 124.7 (d, 3JCH = 4.0
2
2
Hz, ArH), 116.3 (d, JHF = 22.5 Hz, ArH), 114.4 (d, JCF = 18.5 Hz, Ar), 114.0 (ArH), 67.4 (CH2), 55.3
(OCH3), 53.7 (CH), 14.1 (CH3). 19F-NMR (377 MHz, CDCl3, 298 K): −106.3 (m). HR-MALDI-MS (pos.):
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371.0724 ([M + Na]+, C18H17FO4SNa+; calc. 371.0724). Anal. calc. for C18H17FO4S: C 62.06, H 4.92;
found: C 61.88, H 5.02.
4-Methoxybenzyl 3-((2,4-dimethylphenyl)thio)-2-methyl-3-oxopropanoate (4e). According to
general method A on a 0.58 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.2
equiv.), the product was obtained as a colorless oil (166 mg, 80% yield). Analytical data: FT-IR (neat):
2937 (br, C-H arom. and C-H aliph.), 1736 (C=O). 1696 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.37-
7.30 (2 H, m, ArH), 7.24 (1 H, d, 3JHH = 8.0 Hz, ArH), 7.14 (1 H, br s, ArH), 7.06-7.00 (1 H, m, ArH), 6.94-
6.87 (2 H, m, ArH), 5.16 (2 H, s, ArCH2), 3.83 (3 H, s, OCH3), 3.80 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 2.35 (3
H, s, ArCH3), 2.23 (3 H, s, ArCH3), 1.52 (3 H, q, 3JHH = 7.0 Hz, CHCH3). 13C-NMR (100 MHz, CDCl3, 298 K):
193.8 (C=O), 169.2 (C=O), 159.8 (Ar), 142.0 (Ar), 140.7 (Ar), 135.8 (ArH), 131.7 (ArH), 130.2 (ArH),
129.4 (Ar), 127.5 (ArH), 123.0 (Ar), 114.0 (ArH), 67.2 (CH2), 55.3 (OCH3), 53.6 (CH), 21.3 (ArCH3), 20.4
(ArCH3), 14.1 (CH3). HR-MALDI-MS (pos.): 381.1131 ([M + Na]+, C20H22O4SNa+; calc. 381.1131). Anal.
calc. for C20H22O4S: C 67.02, H 6.19, O 17.85; found: C 67.16, H 6.26, O 18.07.
4-Methoxybenzy 3-((4-methoxyphenyl)thio)-3-oxopropanoate (4f). According to general method A
on a 0.28 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.2 equiv.), the product was
obtained as a colorless oil (90 mg, 93% yield). Analytical data: FT-IR (neat): 2936 (br, C-H arom. and
C-H aliph.), 1721 (br, C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.37-7.29 (4 H, m, ArH), 7.00-6.83 (4 H,
m, ArH), 5.15 (2 H, s, ArCH2), 3.84 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 3.68 (2 H, s, CH2). 13C-NMR (100
MHz, CDCl3, 298 K): 190.6 (C=O), 165.8 (C=O), 161.0 (Ar), 159.8 (Ar), 136.2 (ArH), 130.3 (ArH), 127.6
(Ar), 127.3 (Ar), 115.0 (ArH), 114.0 (ArH), 67.3 (CH2), 55.4 (OCH3), 55.3 (OCH3), 48.9 (CH2). HR-ESI-MS
(pos.): 369.0773 ([M + Na]+, C18H18O5SNa+; calc. 369.0767). Anal. calc. for C18H18O5S: C 62.41, H 5.24,
O 23.09; found: C 62.36, H 5.22, O 22.92.
4-Methoxybenzyl 2-(((4-methoxyphenyl)thio)carbonyl)butanoate (4g). According to general
method A on a 0.35 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.5 equiv.), the
product was obtained as a colorless oil (112 mg, 85% yield). Analytical data: FT-IR (neat): 2928 (br,
C-H arom. and C-H aliph.), 1736 (C=O). 1690 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.40-7.18 (4 H,
3
m, ArH), 7.01-6.79 (4 H, m, ArH), 3.84 (3 H, s, OCH3), 3.83 (3 H, s, OCH3), 3,61 (1 H, t, JHH = 7.5 Hz,
CHCH2CH3), 2.08-1.98 (2 H, m, CHCH2CH3), 1.00 (3 H, s, CHCH2CH3). 13C-NMR (100 MHz, CDCl3, 298 K):
194.1 (C=O), 168.5 (C=O), 160.8 (Ar), 159.7 (Ar), 136.1 (ArH), 130.1 (ArH), 127.6 (Ar), 117.7 (Ar),
114.9 (ArH), 113.9 (ArH), 67.1 (CH2), 60.9 (CH), 55.4 (OCH3), 55.3 (OCH3), 23.0 (CH2), 11.8 (CH3). HR-
MALDI-MS (pos.): 397.1078 ([M + Na]+, C20H22O5SNa+; calc. 397.1080). Anal. calc. for C20H22O5S: C
64.15, H 5.92, O 21.36; found: C 64.05, H 5.94, O 21.24.
4-Methoxybenzyl 2-benzyl-3-((4-methoxyphenyl)thio)-3-oxopropanoate (4h). According to general
method A on a 0.18 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.5 equiv.), the
product was obtained as a colorless oil (73 mg, 93% yield). Analytical data: FT-IR (neat): 2936 (br, C-
H arom. and C-H aliph.), 1732 (C=O). 1698 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.33-7.15 (5 H, m,
ArH), 6.98-6.85 (4 H, m, ArH), 6.97-6.86 (4 H, m, ArH), 5.13 (2 H, s, ArCH2), 4.00 (1 H, t, 3JHH = 7.5 Hz,
13
CHCH2Ph), 3.84 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 3.29 (2 H, apt d, J = 7.5 Hz, CHCH2Ph). C-NMR
(100 MHz, CDCl3, 298 K): 193.6 (C=O), 167.9 (C=O), 160.9 (Ar), 159.7 (Ar), 137.4 (Ar), 136.1 (ArH),
130.1 (ArH), 129.0 (ArH), 128.6 (ArH), 127.4 (Ar), 126.9 (ArH), 117.5 (ArH), 114.9 (ArH), 113.9 (ArH),
67.3 (ArCH2O), 61.0 (CH), 55.4 (OCH3), 55.3 (OCH3), 35.3 (ArCH2CH). HR-ESI-MS (pos.): 454.1682
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([M + NH4]+, C25H28NO5S+; calc. 454.1683). Anal. calc. for C25H24O5S: C 68.79, H 5.54, O 18.33; found: C
68.64, H 5.58, O 18.17.
4-Methoxybenzyl 2-(((4-methoxyphenyl)thio)carbonyl)pent-4-enoate (4i). According to general
method A on a 0.18 mmol scale with 1.5 equiv. 4-methoxybenzyl-2,2,2-trichloroacetimidate, the
product was obtained as a colorless oil (60 mg, 86% yield). Analytical data: FT-IR (neat): 2955 (br, C-
H arom. and C-H aliph.), 1737 (C=O). 1699 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.38-7.23 (4 H, m,
ArH), 6.98-6.87 (4 H, m, ArH), 5.79 (1 H, ddt, 3JHH = 17.0 Hz, 3JHH = 10.0 Hz, 3JHH = 7.0 Hz, CHCH2CHCH2),
5.23-5.03 (2 H, m, CHCH2CHCH2), 5.16 (2 H, s, ArCH2), 3.84 (3 H, s, OCH3), 3,83 (3 H, s, OCH3), 3.78 (1
H, t, 3JHH = 7.5 Hz, CHCH2CHCH2), 2.99-2.42 (2 H, m, CHCH2CHCH2). 13C-NMR (100 MHz, CDCl3, 298 K):
193.4 (C=O), 168.0 (C=O), 161.0 (Ar), 159.8 (Ar), 136.1 (ArH), 133.5 (CH), 130.2 (ArH), 127.5 (Ar),
118.1 (CH2), 117.5 (Ar), 115.0 (ArH), 113.9 (ArH), 67.3 (ArCH2), 58.9 (CH), 55.4 (OCH3), 55.3 (OCH3),
33.4 (CH2). HR-ESI-MS (pos.): 404.1527 ([M + NH4]+, C21H26NO5S+; calc. 404.1526). Anal. calc. for
C21H22O5S: C 65.27, H 5.74, O 20.70; found: C 65.40, H 5.81, O 20.97.
4-Methoxybenzyl 2-fluoro-3-((4-methoxyphenyl)thio)-3-oxopropanoate (4j). According to general
method A on a 4.09 mmol scale with 4-methoxybenzyl-2,2,2-trichloroacetimidate (1.2 equiv.), the
product was obtained as a colorless oil (1.40 g, 94% yield). Analytical data: FT-IR (neat): 2958 (br, C-
H arom. and C-H aliph.), 1752 (C=O). 1699 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.53-7.14 (4 H, m,
2
ArH), 7.07-6.80 (4 H, m, ArH), 5.43 (1 H, d, JHF = 48.5 Hz, C(F)H, 5.26 (2 H, s, ArCH2), 3.85 (3 H, s,
OCH3), 3.83 (3 H, s, OCH3). 13C-NMR (100 MHz, CDCl3, 298 K): 191.5 (d, 2JCF = 28.0 Hz, C=O), 163.2 (d,
2JCF = 24.5 Hz, C=O), 161.2 (Ar), 160.0 (Ar), 136.3 (ArH), 130.4 (ArH), 126.5 (Ar), 115.2 (ArH), 115.1 (d,
4JCF = 4.5 Hz, Ar), 114.1 (ArH), 90.8 (d, 1JCF = 202.0 Hz, CF), 68.3 (CH2), 55.4 (OCH3). 19F-NMR (377 MHz,
2
CDCl3, 298 K): −192.2 (d, JHF = 48.5 Hz). HR-MALDI-MS (pos.): 387.0675 ([M + Na]+, C18H17FO5SNa+;
calc. 387.0673). Anal. calc. for C18H17FO5S: C 59.33, H 4.70; found: C 59.19, H 4.76.
tert-Butyl 3-((4-methoxyphenyl)thio)-2-methyl-3-oxopropanoate (4k). According to general method
A on a 0.20 mmol scale with tert-butyl-2,2,2-trichloroacetimidate (1.2 equiv.), the product was
obtained as a colorless oil (56 mg, 91% yield). Analytical data: FT-IR (neat): 2937 (br, C-H arom. and
C-H aliph.), 1734 (C=O). 1699 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.38-7.31 (2 H, m, ArH), 7.00-
6.91 (2 H, m, ArH), 3.84 (3 H, s, OCH3), 3.66 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 1.51 (9 H, s, O(CH3)3), 1.46
(3 H, d, 3JHH = 7.0 Hz, CHCH3). 13C-NMR (100 MHz, CDCl3, 298 K): 195.3 (C=O), 168.4 (C=O), 160.8 (Ar),
136.1 (ArH), 117.8 (Ar), 114.9 (ArH), 82.1 (C), 55.4 (OCH3), 54.5 (CH), 27.9 (CH3), 14.0 (CH3). HR-ESI-
MS (pos.): 319.0979 ([M + Na]+, C15H20O4SNa+; calc. 319.0975). Anal. calc. for C15H20O4S: C 60.79, H
6.80, O 21.59; found: C 60.90, H 6.80, O 21.80.
Allyl 2-fluoro-3-((4-methoxyphenyl)thio)-3-oxopropanoate (4l). According to general method A on a
0.88 mmol scale with allyl-2,2,2-trichloroacetimidate (2 equiv.), the product was obtained as a
colorless oil (163 mg, 65% yield). Analytical data: FT-IR (neat): 2945 (br, C-H arom. and C-H aliph.),
1755 (C=O). 1699 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.38-7.29 (2 H, m, ArH), 7.00-6.93 (2 H, m,
ArH), 5.92 (1 H, ddt, 3JHH = 17.0 Hz, 3JHH = 10.5 Hz, 3JHH = 6.0 Hz, OCH2CHCH2), 5.43 (1 H, d, 2JHF = 48.5
3
3
3
Hz, CHF), 5.38 (1 H, dq, JHH = 17.0 Hz, JHH = 1.5 Hz, OCH2CHCHH), 5.30 (1 H, dq, JHH = 10.5 Hz,
3JHH = 1.5 Hz, OCH2CHCHH), 4.84-4.70 (2 H, m, OCH2CHCH2), 3.83 (3 H, s, OCH3). C-NMR (100 MHz,
CDCl3, 298 K): 191.6 (d, JCF = 28.0 Hz, C=O), 163.1 (d, JCF = 24.5 Hz, C=O), 161.4 (Ar), 136.4 (ArH),
13
2
2
4
1
130.7 (CH), 119.8 (CH2), 115.4 (ArH), 115.2 (d, JCF = 5.0 Hz, Ar), 90.9 (d, JCF = 201.5 Hz, CF), 67.3
(CH2), 55.5 (OCH3). 19F-NMR (377 MHz, CDCl3, 298 K): −192.8 (d, JHF = 48.5 Hz). HR-EI-MS (pos.):
2
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284.0515 ([M]+, C13H13FO4S+; calc. 284.0513). Anal. calc. for C13H13FO4S: C 54.92, H 4.61; found: C
54.66, H 4.63
Benzyl 2-fluoro-3-((4-methoxyphenyl)thio)-3-oxopropanoate (4m). According to general method A
on a 0.96 mmol scale with benzyl-2,2,2-trichloroacetimidate (1.2 equiv.), the product was obtained
as a colorless oil (162 mg, 50% yield). Analytical data: FT-IR (neat): 2960 (br, C-H arom. and C-H
aliph.), 1758 (C=O). 1701 (C=O). 1H-NMR (400 MHz, CDCl3, 298 K): 7.50-7.32 (5 H, m, ArH), 7.32-7.26
(2 H, m, ArH), 7.05-6.85 (2 H, m, ArH), 5.44 (1 H, d, 2JHF = 48.5 Hz, CHF), 5.30 (2 H, s, CH2Ar), 3.83 (3 H,
2
2
s, OCH3). 13C-NMR (100 MHz, CDCl3, 298 K): 191.6 (d, JCF = 28.0 Hz, C=O), 163.2 (d, JCF = 24.5 Hz,
C=O), 161.4 (Ar), 136.5 (ArH), 134.5 (Ar), 128.9 (Ar), 128.8 (ArH), 128.5 (ArH), 115.4 (ArH), 115.2 (d,
4JCF = 4.5 Hz, Ar), 90.9 (d, 1JCF = 201.5 Hz, CF), 68.4 (CH2), 55.5 (OCH3). 19F-NMR (377 MHz, CDCl3, 298
K): −192.2 (d, JHF = 48.5 Hz). HR-EI-MS (pos.): 334.0673 ([M]+, C17H15FO4S+; calc. 334.0675). Anal.
2
calc. for C17H15FO4S: C 61.07, H 4.52; found: C 61.04, H 4.59.
tert-Butyl 2-fluoro-3-((4-methoxyphenyl)thio)-3-oxopropanoate (4n). According to general method
A on a 0.94 mmol scale with tert-butyl-2,2,2-trichloroacetimidate (2 equiv.), the product was
obtained as a colorless oil (219 mg, 77% yield). Analytical data: FT-IR (neat): 2980 (br, C-H arom. and
C-H aliph.), 1752 (C=O). 1706 (C=O). 1H-NMR (400 MHz, CDCl3, 298 K): 7.36-7.22 (2 H, m, ArH), 7.02-
2
13
6.90 (2 H, m, ArH), 5.28 (1 H, d, JHF = 48.5 Hz, CHF), 3.83 (3 H, s, OCH3), 1.52 (9 H, s, C(CH3)3). C-
2
2
NMR (100 MHz, CDCl3, 298 K): 192.0 (d, JCF = 28.0 Hz, C=O), 162.3 (d, JCF = 24.0 Hz, C=O), 136.5
(ArH), 115.6 (d, 4JCF = 4.5 Hz, Ar), 115.4 (ArH), 91.2 (d, 1JCF = 200.5 Hz, CF), 84.9 (C), 55.5 (OCH3), 28.0
(CH3). 19F-NMR (377 MHz, CDCl3, 298 K): −191.3 (d, 2JHF = 48.5 Hz). HR-EI-MS (pos.): 300.0836 ([M]+,
C14H17FO4S+; calc. 300.0826). Anal. calc. for C14H17FO4S: C 55.99, H 5.71, S 10.68, F 6.33; found: C
55.84, H 5.74, S 10.57, F 6.70
Synthesis of MTMs 5a-e
Methyl 3-((4-methoxyphenyl)thio)-2-methyl-3-oxopropanoate (5a). According to general method B
on a 0.12 mmol scale with methyl triflate (1.2 equiv.), the product was obtained as a colorless oil
(29 mg, 94% yield). Analytical data: FT-IR (neat): 2945 (br, C-H arom. and C-H aliph.), 1740 (C=O).
1696 (C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.40-7.31 (2 H, m, ArH), 7.01-6.92 (2 H, m, ArH), 3.84
3
3
(3 H, s, OCH3), 3.79 (3 H, s, OCH3), 3.77 (1 H, q, JHH = 7.0 Hz, CHCH3), 1.52 (3 H, d, JHH = 7.0 Hz,
13
CHCH3). C-NMR (100 MHz, CDCl3, 298 K): 195.0 (C=O), 169.7 (C=O), 160.9 (Ar), 136.1 (ArH), 117.5
(Ar), 115.0 (ArH), 55.4 (OCH3), 53.2 (CH), 52.7 (OCH3), 14.3 (CH3). HR-ESI-MS (pos.): 255.0689
([M + H]+, C12H15O4S+; calc. 255.0686). Anal. calc. for C12H14O4S: C 56.68, H 5.55, O 25.17; found: C
56.60, H 5.54, O 25.34.
Ethyl 3-((4-methoxyphenyl)thio)-2-methyl-3-oxopropanoate (5b). According to general method B
on a 0.12 mmol scale with ethyl triflate (1.2 equiv.), the product was obtained as colorless oil (31 mg,
96% yield). Analytical data: FT-IR (neat): 2982 (br, C-H arom. and C-H aliph.), 1737 (C=O). 1699
(C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.39-7.30 (2 H, m, ArH), 6.96 (2 H, m, ArH), 4.24 (2 H, q, 3JHH
= 7.0 Hz, OCH2CH3), 3.83 (3 H, s, OCH3), 3.75 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 1.51 (3 H, d, 3JHH = 7.0 Hz,
3
13
CHCH3), 1.32 (3 H, t, JHH = 7.0 Hz, OCH2CH3). C-NMR (100 MHz, CDCl3, 298 K): 195.0 (C=O), 169.3
(C=O), 160.9 (Ar), 136.1 (ArH), 117.6 (Ar), 115.0 (ArH), 61.7 (CH2), 55.4 (OCH3), 53.5 (CH), 14.2 (CH3),
14.1 (CH3). HR-ESI-MS (pos.): 269.0845 ([M + H]+, C13H17O4S+; calc. 269.0842). Anal. calc. for
C13H16O4S: C 58.19, H 6.01, O 23.85; found: C 58.16, H 5.99, O 23.98.
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Benzyl 3-((4-methoxyphenyl)thio)-2-methyl-3-oxopropanoate (5c). Benzyl alcohol (1.2 equiv.) and
2,4,6-trimethyl pyridine (1.3 equiv.) were dissolved in CH2Cl2 (2 mL/mmol) at –78 °C. A solution of
trifluoromethanesulfonyl anhydride (1.3 equiv.) in CH2Cl2 (2 mL/mmol) was added dropwise and the
mixture was stirred for 15 min at –78 °C. The solution was added dropwise to a solution of the
malonic acid half thioester (1.0 equiv.) and 2,4,5-trimethyl pyridine (1.3 equiv.) in CH2Cl2 (0.5 M) at –
78 °C. The reaction mixture was stirred for 1 h at –78 °C and quenched with saturated aqueous
ammonium chloride (1 mL/mmol). The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 2.0 mL/mmol). The combined organic phases were dried over Na2CO3, filtered, and
concentrated under reduced pressure. The resulting crude mixture was purified by flash
chromatography on silica, eluting with EtOAc/n-hexane to afford the product as a colorless oil (256
mg, 93% yield). Analytical data: FT-IR (neat): 2939 (br, C-H arom. and C-H aliph.), 1738 (C=O). 1696
(C=O). 1H-NMR (300 MHz, CDCl3, 298 K): 7.44-7.36 (5 H, m, ArH), 7.34-7.29 (2 H, m, ArH), 6.99-6.92 (2
H, m, ArH), 5.24 (2 H, s, ArCH2), 3.85 (3 H, s, OCH3), 3.83 (1 H, q, 3JHH = 7.0 Hz, CHCH3), 1.55 (3 H, d,
13
3JHH = 7.0 Hz, CHCH3). C-NMR (100 MHz, CDCl3, 298 K): 194.8 (C=O), 169.1 (C=O), 160.9 (Ar), 136.2
(ArH), 135.4 (Ar), 128.6 (ArH), 128.4 (ArH), 128.2 (ArH), 117.5 (Ar), 115.0 (ArH), 67.3 (CH2), 55.4
(OCH3), 53.5 (CH), 14.2 (CH3). HR-ESI-MS (pos.): 331.1001 ([M + H]+, C18H19O4S+; calc. 331.0999). Anal.
calc. for C18H18O4S: C 65.44, H 5.49, O 19.37; found: C 65.38, H 5.52, O 19.28.
Methyl 2-fluoro-3-((4-methoxyphenyl)thio)-3-oxopropanoate (5d).
According to general method B on a 15.39 mmol scale with methyl triflate (1.2 equiv.), the product
was obtained as a colorless oil (3.6 g, 91% yield). Analytical data: FT-IR (neat): 2958 (br, C-H arom.
1
and C-H aliph.), 1757 (C=O). 1706 (C=O). H-NMR (300 MHz, CDCl3, 298 K): 7.64-7.34 (2 H, m, ArH),
2
13
7.34-7.08 (2 H, m, ArH), 5.47 (1 H, d, JHF = 48.5 Hz, C(F)H), 3.91 (3 H, s, OCH3). C-NMR (100 MHz,
2
2
1
CDCl3, 298 K): 189.0 (d, JCF = 29.0 Hz, C=O), 163.3 (d, JCF = 24.0 Hz, C=O), 162.3 (d, JCF = 251.0 Hz,
ArF), 136.6 (ArH), 133.0 (d, JCF = 8.0 Hz, ArH), 125.0 (d, JCF = 4.0 Hz, ArH), 116.5 (d, JCF = 22.5 Hz,
ArH), 112.3 (dd, JCF = 18.5 Hz, JCF = 5.5 Hz, Ar), 90.7 (d, JCF = 201.5 Hz, CF), 53.6 (OCH3). F-NMR
(377 MHz, CDCl3, 298 K): –192.3 (d, 2JHF = 48.5 Hz). HR-EI-MS (pos.): 246.0157 ([M + H]+, C10H8F2O3S+;
calc. 246.0162). Anal. calc. for C11H11FO4S: C 51.16, H 4.29; found: C 50.95, H 4.38.
3
4
2
2
4
1
19
Ethyl 2-fluoro-3-((4-methoxyphenyl)thio)-3-oxopropanoate (5e). According to general method B on
a 2.86 mmol scale with ethyl triflate (1.2 equiv.), the product was obtained as a colorless oil (0.73 g,
93% yield). Analytical data: FT-IR (neat): 2981 (br, C-H arom. and C-H aliph.), 1753 (C=O). 1701
(C=O). 1H-NMR (400 MHz, CDCl3, 298 K): 7.38-7.29 (2 H, m, ArH), 7.04-6.90 (2 H, m, ArH), 5.39 (1 H, d,
2JHF = 48.5 Hz, CHF), 4.34 (2 H, q, 3JHH = 7.0 Hz, OCH2CH3), 3.83 (3 H, s, OCH3), 1.33 (3 H, t, 3JHH = 7.0 Hz,
13
2
2
OCH2CH3). C-NMR (100 MHz, CDCl3, 298 K): 191.8 (d, JCF = 28.0 Hz, C=O), 163.4 (d, JCF = 24.0 Hz,
C=O), 161.3 (Ar), 136.4 (ArH), 115.4 (ArH), 115.3 (d, 4JCF = 5.0 Hz, Ar), 91.0 (d, 1JCF = 201.5 Hz, CF), 63.1
(CH2), 55.5 (OCH3), 14.1 (CH3). 19F-NMR (377 MHz, CDCl3, 298 K): −192.8 (d, 2JHF = 48.5 Hz). HR-EI-MS
(pos.): 272.0511 ([M]+, C12H13FO4S+; calc. 272.0513). Anal. calc. for C12H13FO4S: C 52.93, H 4.81;
found: C 52.87, H 4.85.
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Supplementary Material
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/MS-number. ((Please delete this text if not appropriate))
Acknowledgements
We thank the Swiss National Science Foundation and ETH Zürich for supporting this research.
Author Contribution Statement
[+] These Authors contributed equally.
O. D. Engl, J. Saadi and H. Wennemers conceived and designed the project and prepared the
manuscript, which was edited by all authors. O. D. Engl, J. Saadi and E. Cosimi conducted the
experiments and analyzed the data.
References
[1]
[2]
[3]
H. Prokopcovà, C. O. Kappe, ‘The Liebeskind-Srogl C-C cross-coupling reaction’, Angew. Chem. Int. Ed. 2009, 48, 2276–2286.
T. Fukuyama, H. Tokuyama, ‘Palladium-mediated synthesis of aldehydes and ketones from thiol esters’, Aldrichimica Acta 2004, 37, 87–96.
T. Miyazaki, M. Benaglia, M. Cinguini, F. Cozzi, ‘The S-thioester enolate/imine condensation: a shortcut to β-lactams’, Eur. J. Org. Chem. 2000, 4, 563–
572.
[4]
[5]
N. S. McGrath, R. T. Raines, ‘Chemoselectivity in chemical biology: acyl transfer reactions with sulfur and selenium’, Acc. Chem. Res. 2011, 44, 752–761.
W. Yang, D. G. Drueckhammer, ‘Understanding the relative acyl-transfer reactivity of oxoesters and thioesters: computational analysis of transition
state delocalization effects’, J. Am. Chem. Soc. 2001, 123, 11004–11009.
[6]
[7]
[8]
D. J. Hupe, W. P. Jencks, ‘Nonlinear structure-reactivity correlations. acyl transfer between sulfur and oxygen nucleophiles’, J. Am. Chem. Soc. 1997, 99,
451–464.
K. A. Connors, M. L. Bender, ‘The kinetics of alkaline hydrolysis and n-butylaminolysis of ethyl p-nitrobenzoate and ethyl p-nitrothiolbenzoate’, J. Org.
Chem. 1961, 26, 2498–2504.
For examples using chiral boron ketene O,S-acetals, see: C. Gennari, A. Vulpetti, M. Donghai, N. Mongelli, E. Vanotti, ‘Semisynthesis of Taxol: A highly
enantio- and diastereoselective synthesis of the side chain and new method for ester formation at C13 using thioesters’ Angew. Chem. Int. Ed. 1996,
35, 1723−1725 and ref. 9–12.
[9]
C. Gennari, G. Pain, ‘Boron aldol reactions of α-halosubstituted thioacetates with silyl imines: A highly enantio- and diastereoselective synthesis of
aziridines’ Tetrahedron Lett. 1996, 37, 3747−3750.
[10] C. Gennari, D. Moresca, S. Vieth, A. Vulpetti, ‘Computer-assisted design of chiral boron enolates: A novel, highly enantioselective aldol reaction for
thioacetates and thiopropionates’ Angew. Chem. Int. Ed. 1993, 32, 1618−1621.
[11] E. J. Corey, S. S. Kim, ‘Versatile chiral reagent for the highly enantioselective synthesis of either anti or syn ester aldols’ J. Am. Chem. Soc. 1990, 112,
4976−4977.
[12] S. Masamune, T. Sato, B. M. Kim, T. A. Wollmann, ‘Organoboron compounds in organic synthesis. 4. Asymmetric aldol reactions’ J. Am. Chem. Soc.
1986, 108, 8279−8281.
[13] For examples using silyl ketene O,S-acetals, see: A. Claraz, G. Sahoo, D. Berta, Á. Madarász, I. Pápai, P. M. Pihko, ‘A catalyst designed for the
enantioselective construction of methyl- and alkyl-substituted tertiary stereocenters’ Angew. Chem. Int. Ed. 2016, 55, 669−673 and ref. 14 & 15.
This article is protected by copyright. All rights reserved.

[14] T. Harada, S. Adachi, X. Wang, ‘Dimethylsilyl ketene acetal as a nucleophile in asymmetric Michael reaction: Enhanced enantioselectivity in
oxazaborolidinone-catalyzed reaction’ Org. Lett. 2004, 6, 4877−4879.
[15] S. Kobayashi, M. Horibe, Y. Saito, ‘Enantioselective synthesis of both diastereomers, including the α-alkoxy-β-hydroxy-β-methyl(phenyl) units, by chiral
tin(II) Lewis acid-mediated’ Tetrahedron 1994, 50, 9629−9642.
[16] For organocatalyzed examples using electron-poor trifluoroethyl thioesters, see: S. Rossi, M. Benaglia, F. Cozzi, A. Genoni, T. Benincori,
‘Organocatalytic Stereoselective Direct Aldol Reaction of Trifluoroethyl Thioesters’, Adv. Synth. Catal. 2011, 353, 848−854 and ref. 17–19.
[17] M. C. Kohler, J. M. Yost, M. R. Garnsey, D. M. Coltart, ‘Direct Carbon−Carbon Bond Formation via Soft Enolization: A Biomimetic Asymmetric Mannich
Reaction of Phenylacetate Thioesters’, Org. Lett. 2010, 12, 3376−3379.
[18] D. A. Alonso, S. Kitagaki, N. Utsumi, C. B. Barbas, ‘Towards organocatalytic polyketide synthases with diverse electrophile scope: trilfuoroethyl
thioesters as nucleophiles in organocatalytic Michael reactions and beyond’, Angew. Chem. Int. Ed. 2008, 47, 4588–4591.
[19] N. Utsumi, S. Kitagaki, C. B. Barbas, ‘Organocatalytic Mannich-type reactions of trifluoroethyl thioesters’, Org. Lett. 2008, 10, 3405–3408.
[20] For organocatalyzed examples using dithiomalonates, see: J. H. Sim, C. E. Song, ‘Water-enabled catalytic asymmetric Michael reactions of unreactive
nitroalkenes: One-pot synthesis of chiral GABA-analogs with all-carbon quaternary stereogenic centers’ Angew. Chem. Int. Ed. 2017, 56, 1835−1839
and ref. 21–26.
[21] H. Jin, S. T. Kim, G.-S. Hwang, D. H. Ryu, ‘L-proline derived bifunctional organocatalysts: Enantioselective Michael addition of dithiomalonates to trans-
β-nitroolefins’ J. Org. Chem. 2016, 81, 3263−3274.
[22] H. Y. Bae, M. J. Kim, J. H. Sim, C. E. Song, ‘Direct catalytic asymmetric Mannich reaction with dithiomalonates as excellent Mannich donors:
Organocatalytic synthesis of (R)-Sitagliptin’ Angew. Chem. Int. Ed. 2016, 55, 10825−10829.
[23] M. Hatano, K. Moriyama, T. Maki, K. Ishihara, ‘Which is the actual catalyst: Chiral phosphoric acid or chiral calcium phosphate’ Angew. Chem. Int. Ed.
2010, 49, 3823−3826.
[24] Z. Jiang, Y. Yang, Y. Pan, Y. Zhao, H. Liu, C.-H. Tan, ‘Synthesis of α-stereogenic amides and ketones by enantioselective conjugate addition of 1,4-
dicarbonyl but-2-enes’, Chem. Eur. J. 2009, 15, 4925–4930.
[25] J. Xu, X. Fu, R. Low, Y.-P. Goh, Z. Jiang, C.-H. Tan, ‘Tandem conjugate addition-elimination reaction promoted by chiral pyrrolidinyl sulfonamide (CPS)’,
Chem. Commun. 2008, 5526–5528.
[26] W. Ye, Z. Jiang, Y. Zhao, S. L. M. Goh, D. Leow, Y.-T. Soh, C.-H. Tan, ‘Chiral bicyclic guanidine as a versatile Brønsted base catalyst for the
enantioselective Michael reactions of dithiomalonates and β-keto thioesters’, Adv. Synth. Catal. 2007, 349, 2454–2458.
[27] Y. Kobuke, J.-i. Yoshida, ‘Decarboxylative acylation of thiomalonate. A model for the biosynthesis of fatty acids and polyketides’ Tetrahedron Lett.
1978, 19, 367–370.
[28] N. Sakai, N. Sordé, S. Matile, ‘Mg2+-imidazole-catalyzed self-condensation of malonyl thioesters: getting tuned for biomimetic polyketide synthesis?’
Molecules 2001, 6, 845–851.
[29] F. Berrué, S. Antoniotti, O. P. Thomas, P. Amade, ‘Bioinspired Metal-Catalysed Doebner–Knoevenagel Condensations between Malonic Acid Half
Thioesters and Aldehyde’, Eur. J. Org. Chem. 2007, 1743–1748.
[30] K. C. Fortner, M. D. Shair, ‘Stereoelectronic effects dictate mechanistic dichotomy between Cu(II)-catalyzed and enzyme-catalyzed reactions of malonic
acid half thioesters’, J. Am. Chem. Soc. 2007, 129, 1032–1033.
[31] D. Magdziak, G. Lalic, H. M. Lee, K. C. Fortner, A. D. Aloise, M. D. Shair, ‘Catalytic enantioselective thioester aldol reactions that are compatible with
protic functional groups’, J. Am. Chem. Soc. 2005, 127, 7284–7285.
[32] G. Lalic, A. D. Aloise, M. D. Shair, ‘An exceptionally mild catalytic thioester aldol reaction inspired by polyketide biosynthesis’ J. Am. Chem. Soc. 2003,
125, 2852–2853.
[33] S. Orlandi, M. Benaglia, F. Cozzi, ‘Cu(II)-catalyzed enantioselective aldold condensation between malonic acid hemithioesters and aldehydes’
Tetrahedron Lett. 2004, 45, 1747–1750.
[34] For first examples of stereoselective organocatalytic reactions with MAHTs, see: J. Lubkoll, H. Wennemers, ‘Mimicry of polyketide synthases –
enantioselective 1,4-addition reactions of malonic acid half-thioesters to nitroolefins’, Angew. Chem. Int. Ed. 2007, 46, 6841–6844 and ref. 35.
[35] A. Ricci, D. Petterson, L. Bernardi, F. Fini, M. Fochi, R. P. Herrera, V. Sgarzani, ‘Organocatalytic enantioselective decarboxylative addition of malonic acid
half thioesters to imines’, Adv. Synth. Catal. 2007, 349, 1037–1040.
[36] H. Y. Bae, S. Sonne, J. H. Lee, J.-Y. Kim, M. J. Song, S. Lee, Y. J. Zhang, C. E. Song, ‘Organocatalytic enantioselective Michael-addition of malonic acid half-
thioesters to β-nitroolefins: from mimicry of polyketide synthases to scalable synthesis of γ-amino acids’, Adv. Synth. Catal. 2011, 353, 3196–3202.
This article is protected by copyright. All rights reserved.

[37] Y. Zhao, S. Benz, N. Sakai, S. Matile, ‘Selective acceleration of disfavored enolate addition reactions by anion-π interactions‘, Chem. Sci. 2015, 6, 6219–
6223.
[38] Y. Cotelle, V. Lebrun, N. Sakai, T. R. Ward, S. Matile, ‘Anion-π Enzymes’ ACS Cent. Sci. 2016, 2, 399–393
[39] Q. Ren, S. Sun, J. Huang, W. Li, M. Wu, H. Guo, J. Wang, ‘An enantioselective cascade reaction between α,β-unsaturated aldehydes and malonic half-
thioesters: a rapid access to chiral δ-lactones’, Chem. Commun. 2014, 50, 6137–6140.
[40] S. Nakamura, A. Toda, M. Sano, T. Hatanaka, Y. Funahashi, ‘Organocatalytic enantioselective conjugate addition of malonic acid half thioesters to
coumarin-3-carboxylic acids using N-heteroarenesulfonyl cinchona alkaloid amides’, Adv. Synth. Catal. 2016, 358, 1029–1034.
[41] Q. Ren, T. Gao, W. Li, L. Wan, Y. Hu, Y. Peng, S. Sun, L. Hu, M. Wu, H. Guo, J. Wang, ‘A highly enantioselective Michael reaction between α,β-
unsaturated ketones and malonic acid half-thioesters’, New. J. Chem. 2015, 39, 5100–5103.
[42] S. Nakamura, M. Sano, A. Toda, D. Nakane, H. Masuda, ‘Organocatalytic enantioselective decarboxylative reaction of malonic acid half thioesters with
cyclic N-sulfonyl ketimines by using N-heteroarenesulfonyl cinchona alkaloid amides’, Chem. Eur. J. 2015, 21, 3929–3932.
[43] N. Hara, S. Nakamura, M. Sano, R. Tamura, Y. Funahashi, N. Shibata, ‘Enantioselective synthesis of AG-041R by using N-heteroarenesulfonyl cinchona
alkaloid amides as organocatalysts’, Chem. Eur. J. 2012, 18, 9276–9280.
[44] Y. Pan, C. W. Kee, Z. Jiang, T. Ma, Y. Zhao, Y. Yang, H. Xue, C.-H. Tan, ‘Expanding the utility of Brønsted base catalysis: biomimetic enantioselective
decarboxylation reactions’, Chem. Eur. J. 2011, 17, 8363–8370.
[45] N. Hara, S. Nakamura, Y. Funahashi, N. Shibata, ‘Organocatalytic enantioselective decarboxylative addition of malonic acids half thioesters to isatins’,
Adv. Synth. Catal. 2011, 353, 2976–2980.
[46] H. Y. Bae, J. H. Sim, J.-W. Lee, B. List, C. E. Song, ‘Organocatalytic enantioselective decarboxylative aldol reaction of malonic acid half thioesters with
aldehydes’, Angew. Chem. Int. Ed. 2013, 52, 12143–12147.
[47] J. Saadi, H. Wennemers, ‘Enantioselective aldol reactions with masked fluoroacetates’, Nature Chem. 2016, 8, 276–280.
[48] P. Clerici, H. Wennemers, ‘Mono thiomalonates as thioester enolate equivalents – enantioselective 1,4-addition reactions to nitroolefins under mild
conditions’, Org. Biomol. Chem. 2012, 10, 110–113.
[49] E. Cosimi, J. Saadi, H. Wennemers, ‘Stereoselective synthesis of α-fluoro-γ-nitrothioesters under organocatalytic conditions’, Org. Lett. 2016, 18, 6014–
6017.
[50] Y. Arakawa, S. P. Fritz, H. Wennemers, ‘Organocatalytic stereoselective synthesis of acyclic γ-nitrothioesters with all-carbon quaternary stereogenic
centers’, J. Org. Chem. 2014, 79, 3937–3945.
[51] E. Cosimi, O. D. Engl, J. Saadi, M.-O. Ebert, H. Wennemers, ‘Stereoselective organocatalyzed synthesis of α-fluorinated β-amino thioesters and their
application in peptide synthesis’, Angew. Chem. Int. Ed. 2016, 55, 13127–13131.
[52] Y. Wang, M. Mo, K. Zhu, C. Zheng, H. Zhang, W. Wang, Z. Shao, ‘Asymmetric synthesis of syn-propargylamines and unsaturated β-amino acids under
Brønsteg base catalysis’, Nat. Commun. 2015, 6, 8544.
[53] A. Bahlinger, S. P. Fritz, H. Wennemers, ‘Stereoselective metal-free synthesis of β-amino thioesters with tertiary and quaternary stereogenic centers’,
Angew. Chem. Int. Ed. 2014, 53, 8779–8783.
[54] A. Kolarovic, H. Wennemers, ‘Stereoselective synthesis of indoles via organocatalytic thioester enolate addition reactions’, Org. Lett. 2014, 16, 4236–
4239.
[55] O. D. Engl, S. P. Fritz, A. Käslin, H. Wennemers, ‘Organocatalytic route to dihydrocoumarins and dihydroquinolinones in all stereochemical
configurations’, Org. Lett. 2014, 16, 5454–5457.
[56] O. D. Engl, S. P. Fritz, H. Wennemers, ‘Stereoselective organocatalytic synthesis of oxindoles with adjacent tetrasubstituted stereocenters’, Angew.
Chem. Int. Ed. 2015, 127, 8311–8315.
[57] T. Liu, W. Liu, X. Li, F. Peng, Z. Shao, ‘Catalytic asymmetric construction of vicinal tetrasubstituted stereocenters by the Mannich reaction of linear
α-substituted monothiomalonates with isatin N-Boc ketimines’, J. Org. Chem. 2015, 80, 4950–4956.
[58] F. G. Bordwell, ‘Equilibrium acidities in dimethyl sulfoxide solution’, Acc. Chem. Res. 1988, 21, 456–463.
[59] A. Hill, ‘The biosynthesis, molecular genetics and enzymology of the polyketide-derived metabolites’, Nat. Prod. Rep. 2006, 23, 256-320.
[60] J. Staunton, K. J. Weissman, ‘Polyketide biosynthesis: a millennium review’, Nat. Prod. Rep. 2001, 18, 380–416.
[61] K. Matsuo, M. Shindo, ‘Efficient Synthesis of Dissymmetric Malonic Acid S,O-Esters via Monoalcoholysis of Symmetric Dithiomalonates under Neutral
Conditions’, Org. Lett. 2011, 13, 4406–4409.
This article is protected by copyright. All rights reserved.

[62] H. Brunner, J. Müller, J. Spitzer, ‘Enantioselective catalysis, C[1]. Decarboxylation of malonic acids in the presence of copper(I) compounds – not a
copper(I) catalysis but a base effect’, Monatsh. Chem. 1996, 127, 845–858.
[63] B. Rigo, D. Fasseur, P. Cauliez, D. Couturier, ‘Reaction of trimethylsilyl derivatives with Meldrum’s acid: a new easy monofunctionalization of malonic
acid’, Tetrahedron Lett. 1989, 30, 3072–3076.
[64] N. L. Pohl, R. S. Gokhale, D. E. Cane, C. Khosla, ‘Synthesis and incorporation of an N-acetylcysteamine analogue of methylmalonyl-CoA by a modular
polyketide synthase’, J. Am. Chem. Soc. 1998, 120, 11206–11207.
[65] J. P. Shah, C. M. Russo, K. T. Howard, J. D. Chisholm, ‘Spontaneous formation of PMB esters using 4-methoxybenzyl-2,2,2-trichloroacetimidate’,
Tetrahedron Lett. 2014, 55, 1740–1742.
[66] M. Shoji, T. Uno, H. Kakeya, R. Onose, I. Shiina, H. Osada, Y. Hayashi, ‘Enantio-and diastereoselective total synthesis of EI-1941-1, -2 and -3, inhibitors of
interleukin-1β converting enzymes, and biological properties of their derivatives’, J. Org. Chem. 2005, 70, 9905–9915.
[67] M. Shoji, T. Uno, Y. Hayashi, ‘Stereoselective total synthesis of ent-El-1941-2 and epi-ent-El-1941-2’, Org. Lett. 2004, 6, 4535–4538.
[68] J. Gebauer, S. Arseniyadis, J. Cossy, ‘A concise total synthesis of melithiazole C’, Org. Lett. 2004, 6, 4535–4538.
[69] J. M. Berry, L. D. Hall, ‘Fluorinated sulphonates: Ether formation using benzyl and methyl
trifluoromethanesulphonate (triflate)’, Carbohydrate Res. 1976, 47, 307–310.
This article is protected by copyright. All rights reserved.