Organocatalytic synthesis of optically active aryllactic acid derivatives from β-ketosulfoxides

Article abstract of DOI:10.1080/17415993.2014.946506

The organocatalytic synthesis of new α-acyloxy-3-arylpropionic thioesters has been accomplished providing some enantioenriched important aryllactic acid derivatives in good yield and enantioselectivities.

Full text of DOI:10.1080/17415993.2014.946506

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Organocatalytic synthesis of optically
active aryllactic acid derivatives from
β-ketosulfoxides
Francesca Capittaa, Nicola Melisa, Francesco Seccia, Giuseppe
Romanazzib & Angelo Frongiaa
a Dipartimento di Scienze Chimiche e Geologiche, Università degli
Studi di Cagliari, Complesso Universitario di Monserrato, S.S. 554,
Bivio per Sestu, I-09042 Monserrato (Cagliari), Italy
b DICATECh-Politecnico di Bari, Via Orabona, 4-70125 Bari, Italy
Published online: 12 Aug 2014.
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To cite this article: Francesca Capitta, Nicola Melis, Francesco Secci, Giuseppe Romanazzi &
Angelo Frongia (2014) Organocatalytic synthesis of optically active aryllactic acid derivatives from
β-ketosulfoxides, Journal of Sulfur Chemistry, 35:6, 649-660, DOI: 10.1080/17415993.2014.946506
To link to this article: http://dx.doi.org/10.1080/17415993.2014.946506
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Journal of Sulfur Chemistry, 2014
Vol. 35, No. 6, 649–660, http://dx.doi.org/10.1080/17415993.2014.946506
Organocatalytic synthesis of optically active aryllactic acid
derivatives from β-ketosulfoxides
Francesca Capittaa, Nicola Melisa, Francesco Seccia, Giuseppe Romanazzib and Angelo Frongiaa∗
aDipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Complesso
Universitario di Monserrato, S.S. 554, Bivio per Sestu, I-09042 Monserrato (Cagliari), Italy; bDICATECh-
Politecnico di Bari, Via Orabona, 4-70125 Bari, Italy
(Received 19 June 2014; accepted 16 July 2014)
Dedicated to Professor Pier Paolo Piras on the occasion of his retirement
The organocatalytic synthesis of new α-acyloxy-3-arylpropionic thioesters has been accomplished pro-
viding some enantioenriched important aryllactic acid derivatives in good yield and enantioselectivities.
O
OH
O
S
O
O
1) Pummerer reaction
O
Ar
R
PhS
Ar
Ar
Ph
2) tandem
O
O
acylmigration/EP
optically active
pharmaceutically important
synthetic building blocks
optically active
75-97%yield
85-89%ee
Keywords: asymmetric catalysis; protonation; rearrangement; sulfur; tandem reaction
1. Introduction
Optically active 3-phenyllactic acids and derivatives are a biologically and pharmaceutically
relevant class of building blocks [1,2]: they have been targeted as intermediates for the total
synthesis of bioactive peptides such as hirsutellide A,[3,4] cryptophycins [5–9] and cyclooc-
tadepsipeptides PF1022A [10] and have been used as starting materials for the synthesis of
anti-HIV natural products [11,12] and potential anti-diabetic agents.[13]
A certain number of methods are reported in the literature for their synthesis in non-racemic
form that include strategies involving (Scheme 1): enzymatic and biomimetic methods;[14–16]
reduction of α-keto esters;[17,18] Friedel–Crafts reactions;[19] Sharpless dihydroxylation of
substituted cinnamate esters;[20] 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO)-mediated oxi-
dation of optically active glycols [21] and the chiral pool approach, based on the diazotization
∗Corresponding author. Email: afrongia@unica.it
This article makes reference to supplementary material available on the publisher’s website at http://dx.doi.org/
10.1080/17415993.2014.946506.
c
ꢀ 2014 Taylor & Francis

650 F. Capitta et al.
of the corresponding naturally occurring amino acid derivative.[22,23] In this context, an
organocatalytic protocol (for a general review on asymmetric organocatalysis, see [24–30]) that
provides for the efficient preparation of such products from readily available materials is highly
desirable.
O
O
Ar
R
OH
reduction of
O
HO
Ar
keto esters
O
Ar
R
TEMPO mediated
oxidation
O
1) Sharpless
dihydroxylation
2) hydrogenolysis
OH
Ar
O
NH2
R
O
O
Ar
R
R2
O
O
+
chiral pool approach
OAc
COOR
R1
PhS
Ar
Friedel-Crafts
reactions
O
optically active
this work
O
S
O
Ar
Ph
Ar
O
Ar
H Catalyst
Pummerer
reaction
PhS
PhS
O
O
O
O
O
PhS
O
Ar
Catalyst
intramolecular
acylmigration
enantioselective
protonation
OAc
racemic
Scheme 1. Synthesis of optically active 3-phenyllactate and derivatives.
Recently, we developed an efficient synthesis of α-acyloxy thioesters from β-ketosulfoxides
([31]; for seminal studies on tandem processes involving enantioselective organocatalytic
enol-keto tautomerisation, see [32]; for a diastereoselective approach, see [33,34]) through
a Pummerer reaction [35,36] followed by an enantioselective organocatalytic tandem acyl
migration/enantioselective protonation (for reviews on enantioselective protonation, see [37–
42]; for personal research accounts, see [43–46]). This finding resulted in an operationally
attractive method for the synthesis of such reaction products which could be easily transformed
into sulfur-free derivatives without racemization. Thus, as part of an extension of our work, we
planned the application of this methodology to the preparation of some chiral aryllactic acid
derivatives.
2. Results and discussion
A selection of α-acyloxy-β-ketosulfides 2a–h was prepared from the corresponding
β-ketosulfoxides 1a–h in reasonable overall yields by a Pummerer reaction (Scheme 2). Initially,

Journal of Sulfur Chemistry 651
α-acyloxy-β-ketosulfide 2a was selected as a model compound for catalyst screening and eval-
uation (Table 1). Pleasingly, the expected product 3a was obtained with good chemical yield
(84%) and enantioselectivity (85% ee) when quinidine (10 mol%) was used as catalyst at room
temperature in 0.25 mL of toluene (Table 1, Entry 1).
Scheme 2. Synthesis of α-acyloxy-β-ketosulfides 2a–h.
In an effort to improve the stereoselectivity control, different cinchona alkaloids were eval-
uated. Hydroquinidine (Entry 3) gave results comparable with those of quinidine, while the
reaction in the presence of β-isocupreidine (Entry 2) displayed excellent yield (98%) albeit
with poor enantioselectivity (−32% ee). Unfortunately, the results obtained with biscinchona
alkaloids (DHQD)2PHAL, (DHQD)2AQN and (DHQD)2PYR did not bring any appreciable
improvement of asymmetric induction (Entries 4–6). Further screening of reaction conditions,
using different catalyst loading as well as substrate concentration (Entries 7–9), revealed that
optimum yield and enantioselectivity of 3a was obtained with 10 mol% of quinidine in 0.5 mL
of toluene (Entry 7). However, it should be noted that the catalyst loading could be reduced to
5 mol% without any detrimental effect on the selectivity, although with concomitant increasing
reaction time (Entry 8).
Next, the substituent tolerance in the phenyl ring was investigated in a series of rearrangement
experiments (Scheme 3) using optimized reaction conditions for examining the substrate scope.
Table 1. Optimization of reaction conditionsa.
O
O
PhS
Catalyst (x mol%)
Toluene, RT
O
O
PhS
O
O
2a
Entry Catalyst (x mol%) Time (h) Yield(%)b
3a
Ee (%)c
1
2
3
4
5
6
7d
8d
9d
Quinidine (10)
β-isocupreidine (10)
Hydroquinidine (10)
(DHQD)2PHAL (10)
(DHQD)2AQN (10)
(DHQD)2PYR (10)
Quinidine (10)
4
20
5
18
24
9
8
48
4
84
98
85
67
95
99
90
93
93
85
−32
83
−82
Racemic
−68
87
Quinidine (5)
Quinidine (20)
87
80
aReaction conditions: 2a (0.0675 mmol), catalyst (x mol%) in toluene (0.25 mL) at room
temperature.
bIsolated yield after chromatography.
cDetermined by HPLC analysis using a chiral stationary column.
d0.5 mL of toluene was used.

652 F. Capitta et al.
Gratifyingly, the reactions of 2b–h proceeded with uniform chemical yields and enantioselectiv-
ities, regardless of the steric and electronic properties of the substituents on the phenyl ring, to
give the desired α-acyloxy thioester adducts 3b–h in good to high yields and enantioselectivities.
Scheme 3. Scope of the reaction. aReaction conditions: 2 (0.0675 mmol), quinidine (10 mol%)
in toluene (0.5 mL) at room temperature. Yields are given for isolated materials after column
chromatography. bQuinine was used as catalyst.
Preliminary studies on the application of our methodology were carried out to accomplish
the asymmetric synthesis of derivatives 4–6 (Scheme 4). (R)-2-hydroxy-3-phenylpropanoic acid
benzyl ester 4, a key precursor of hirsutellide A (antimycobacterial cyclohexadepsipeptide),[3,4]
was obtained from 3a, by treatment with benzyl alcohol, in 35% non-optimized yield. On the
other hand, α-hydroxy methylester 5, an important fragment (unit-B) of cryptophycin-24 [5–9]
(tumor selective cytotoxin), was synthesized with the S configuration, from ent-3c in 70% yield
by using K2CO3 in methanol at room temperature. Meanwhile, using the method described in
Scheme 4, we were also able to prepare (R)-methyl 3-(4-fluorophenyl)-2-hydroxypropanoate 6
that is a key building block for the synthesis of various human rhinovirus 3C protease (3CP)
inhibitors [47–49] such as rupintrivir (AG7088).
3. Conclusions
In conclusion, we have developed an efficient and simple route to α-acyloxy-3-arylpropionic
thioester derivatives, which can be transformed into the corresponding optically active aryl-
lactic acid derivatives. This method provides a new entry to this class of α-hydroxy acid
derivatives (for selected recent general stereoselective synthesis of α-hydroxy acids and their
derivatives, see [50–55]; also of interest in this respect is [32]) from easily available materials;
and moreover, it has been demonstrated to be applicable to the synthesis of biologically and
pharmaceutically important synthetic building blocks, such as derivatives 4–6, in good yield and
enantioselectivities.

Journal of Sulfur Chemistry 653
a
a
a
Scheme 4. Synthesis of aryllactic acid derivatives 4–6.
4. Experimental
4.1. General methods
1H NMR spectra were recorded at 500 and 400 MHz at ambient temperature with CDCl3 as
solvent. Data are reported as follows: chemical shifts (δ), multiplicity, coupling constants and
integration. 13C NMR spectra were recorded operating, respectively, at 125 or 100 MHz at
ambient temperature with CDCl3 as solvent. Infrared (IR) spectra were recorded on an FT-IR
spectrophotometer. Low resolution mass spectral analyses were recorded in electron impact ion-
ization (70 eV) mode. Relative intensities are given in parentheses. The high resolution mass

654 F. Capitta et al.
spectrometry (HRMS) analyses were performed using a Bruker micro-TOF QII mass spectrom-
eter equipped with an electrospray ion source (ESI) operated in positive ion mode. The sample
solutions (CH3OH) were introduced by continuous infusion with a syringe pump at a flow rate
of 180 μL min−1. The instrument was operated with end-plate offset and capillary voltages set to
−500 and −4500 V, respectively. The nebulizer pressure was 0.4 bar (N2), and the drying gas
(N2) flow rate was 4.0 L min−1. The capillary exit and skimmer voltages were 90 and 30 V,
respectively. The drying gas temperature was set at 180◦C. The calibration was carried out
with a sodium formate solution (10 mM NaOH in isopropanol/water 1:1 (+0.2% HCOOH))
and the software used for the simulations was Bruker Daltonics DataAnalysis (version 4.0).
Enantiomeric excesses of α-acyloxy thioester were determined by HPLC, using a Chiralpak
AD-H or Chiralcel OJ analytical column with i-PrOH/hexane as eluent, using authentic racemic
samples for reference comparison. Analytical thin layer chromatography was performed using
0.25 mm silica gel 60-F plates. Flash chromatography was performed using columns of 230–400
mesh silica gel 60 (0.040–0.063 mm). Yields refer to chromatographically pure materials. All
spectroscopic data of compounds 4, 5, 6 matched those reported previously in the literature.
4.2. General procedure for the synthesis of α-acyloxy-β-ketosulfides (2a–h)
Acetic anhydride (0.504 mmol) is added followed by methanesulfonic acid (0.0252 mmol) to a
stirred solution of β-ketosulfoxide 1a–h (0.252 mmol) in dichloromethane (2 mL) at 0◦C and
stirring is continued at the same temperature for 1 h and then at room temperature for 2 h. The
reaction mixture is washed successively with saturated NaHCO3 aqueous solution and saturated
NaCl aqueous solution, and dried over anhydrous Na2SO4. The solvent is removed under reduced
pressure and the resulting residue chromatographed on silica gel (mixture of hexane/ether) to
give the corresponding α-acyloxy-β-ketosulfide 2a–h (65–75% yield).
4.2.1. 2-Oxo-3-phenyl-1-(phenylthio)propyl acetate (2a)
1
Pale yellow oil. IR (neat): 3032, 1737, 1439, 1213 cm−1. H NMR (500 MHz, CDCl3) δ: 2.15
(s, 3H), 3.86 (s, 2H), 6.26 (s, 1H), 7.13 (d, J = 10.0 Hz, 2H), 7.24–7.32 (m, 6H), 7.45 (d, J =
10.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ: 20.8, 45.8, 81.2, 127.3, 128.7, 129.2, 129.3, 129.7,
130.0, 132.9, 133.6, 169.8, 197.0. MS (m/z): 191 (M+−109 (31)), 163 (40), 109 (38), 91 (35),
65 (26), 43 (100).
4.2.2. 2-Oxo-1-(phenylthio)-3-(p-tolyl)propyl acetate (2b)
1
Pale yellow oil. IR (neat): 2922, 1737, 1520, 1222 cm−1. H NMR (500 MHz, CDCl3) δ: 2.15
(s, 3H), 2.30 (s, 3H), 3.82 (s, 2H), 6.26 (s, 1H), 7.05 (dd, J = 35.0, 10.0 Hz, 4H), 7.30–7.32 (m,
3H), 7.45 (dd, J = 10.0, 5.0 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ: 20.8, 21.1, 45.5, 81.2,
129.1, 129.3, 129.4, 129.6, 133.6, 136.9, 169.7, 197.2. MS (m/z): 254 (M+−60 (35)), 226 (38),
193 (20), 178 (12), 149 (100), 134 (27), 123 (31), 117 (82), 109 (41), 105 (61), 91 (39), 77 (51),
39 (31).
4.2.3. 3-(4-Methoxyphenyl)-2-oxo-1-(phenylthio)propyl acetate (2c)
1
Yellow oil. IR (neat): 2934, 1737, 1511, 1252 cm−1. H NMR (500 MHz, CDCl3) δ: 2.16 (s,
3H), 3.77 (s, 3H), 3.80 (s, 2H), 6.26 (s, 1H), 6.82 (d, J = 5.0 Hz, 2H), 7.05 (d, J = 10.0 Hz, 2H),
7.25–7.34 (m, 3H), 7.45–7.46 (m, 2H). 13C NMR (125 MHz, CDCl3) δ: 20.8, 45.0, 55.3, 81.2,

Journal of Sulfur Chemistry 655
114.2, 124.9, 129.2, 129.3, 130.1, 130.8, 133.6, 158.9, 169.8, 197.4. MS (m/z): 330 (M+ (3)),
221 (85), 193 (100), 161 (30), 152 (28), 121 (82), 101 (23), 91 (10), 77 (12), 65 (12), 43 (60).
4.2.4. 3-(4-Fluorophenyl)-2-oxo-1-(phenylthio)propyl acetate ( 2d)
1
Yellow oil. IR (neat): 3062, 2926, 1737, 1511, 1226 cm−1. H NMR (400 MHz, CDCl3) δ:
2.18 (s, 3H), 3.85 (q, J = 16.0 Hz, 2H), 6.27 (s, 1H), 6.95–7.00 (m, 2H), 7.07–7.10 (m, 2H),
7.32–7.35 (m, 3H), 7.46–7.48 (m, 2H) 13C NMR (100 MHz, CDCl3) δ: 20.7, 44.7, 81.2, 115.3,
115.5, 128.5, 129.2, 129.3, 129.8, 131.2, 131.3, 133.5, 163.3, 169.8, 196.8. MS (m/z): 209
(M+−109 (49)), 181 (44), 149 (2), 110 (42), 101 (4), 83 (6), 65 (8), 43 (100), 39 (3).
4.2.5. 2-Oxo-1-(phenylthio)-3-(4-(trifluoromethyl)phenyl)propyl acetate ( 2e)
Yellow oil. IR (neat): 3066, 2922, 1754, 1729, 1328 cm−1. 1H NMR (400 MHz, CDCl3) δ: 2.19
(s, 3H), 3.93 (ABq, J = 16.0, 44.0 Hz, 2H), 6.25 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.29–7.35
(m, 3H), 7.44 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ:
20.8, 45.2, 81.5, 125.4, 125.53, 125.57, 125.6, 129.40, 129.44, 130.1, 133.6, 136.9, 169.9, 196.1.
MS (m/z): 259 (M+−109 (22)), 231 (18), 159 (11), 109 (44), 91 (5), 77 (5), 65 (15), 43 (100).
4.2.6. 3-([1,1ꢁ-Biphenyl]-4-yl)-2-oxo-1-(phenylthio)propyl acetate ( 2f)
Pale yellow oil. IR (neat): 3032, 1754, 1733, 1486, 1226 cm−1. 1H NMR (400 MHz, CDCl3) δ:
2.19 (s, 3H), 3.92 (d, J = 4.0 Hz, 2H), 6.30 (s, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.31–7.35 (m, 3H),
7.40–7.48 (m, 5H), 7.54 (dd, J = 16.0, 8.0 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ: 20.9, 45.4,
81.4, 127.1, 127.42, 127.46, 128.8, 129.2, 129.4, 130.0, 130.2, 131.9, 133.6, 140.3, 140.8, 169.9,
197.0. MS (m/z): 318 (M+−58 (17)), 209 (37), 191 (5), 167 (100), 152 (26), 123 (37), 109 (10),
77 (14), 65 (10), 45 (19), 39 (6).
4.2.7. 2-Oxo-1-(phenylthio)-3-(m-tolyl)propyl acetate (2g)
Pale yellow oil. IR (neat): 3028, 2922, 1750, 1729, 1213 cm−1. 1H NMR (400 MHz, CDCl3) δ:
2.16 (s, 3H), 2.29 (s, 3H), 3.83 (s, 2H), 6.27 (s, 1H), 6.92–7.19 (m, 4H), 7.31–7.47 (m, 5H).
13C NMR (100 MHz, CDCl3) δ: 20.7, 21.3, 45.6, 81.1, 126.7, 127.9, 128.4, 129.0, 129.2, 130.4,
132.7, 133.5, 134.5, 138.1, 169.6, 197.0. MS (m/z): 254 (M+−60 (51)), 226 (7), 193 (3), 145
(7), 117 (100), 109 (28), 91 (27), 77 (19), 65 (28), 58 (15), 39 (15).
4.2.8. 2-Oxo-1-(phenylthio)-3-(o-tolyl)propyl acetate (2h)
1
Yellow oil. IR (neat): 3020, 1759, 1703, 1448, 1443, 1222 cm−1. H NMR (400 MHz, CDCl3)
δ: 2.17 (s, 6H), 3.90 (s, 2H), 6.25 (s, 1H), 7.05–7.17 (m, 4H), 7.32–7.48 (m, 5H). 13C NMR
(100 MHz, CDCl3) δ: 19.6, 20.8, 44.1, 81.4, 126.2, 127.7, 129.1, 129.2, 129.4, 130.5, 130.7,
131.7, 133.4, 137.4, 169.9, 197.0. MS (m/z): 254 (M+−60 (59)), 226 (29), 193 (9), 178 (5), 149
(86), 117 (100), 115 (98), 109 (37), 91 (40), 87 (41), 65 (43), 49 (28), 39 (24).
4.3. General procedure for the synthesis of optically active α-acyloxy thioester 3a–h
To a solution of 2a–h (0.0675 mmol) in toluene (0.5 mL) was added quinidine (2.17 mg,
0.00675 mmol), and the mixture was stirred for 8–9 h at room temperature. The crude reaction

656 F. Capitta et al.
mixture was directly loaded on silica gel column without aqueous work-up and pure products
were obtained by flash column chromatography (silica gel, mixture of hexane/ether).
4.3.1. 1-Oxo-3-phenyl-1-(phenylthio)propan-2-yl acetate (3a)
Yield 90%; pale yellow oil. IR (neat): 3037, 1759, 1703, 1443, 1217 cm−1. [α]D20 = +114.5
(c 1.45, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 2.07 (s, 3H), 3.12 (ddd, J = 20.0, 15.0, 5.0 Hz,
2H), 5.47 (dd, J = 10.0, 5.0 Hz, 1H), 7.15–7.34 (m, 10 H). 13C NMR (125 MHz, CDCl3) δ: 20.8,
38.3, 78.7, 126.4, 127.2, 128.6, 129.4, 129.6, 129.7, 134.8, 135.5, 169.8, 196.8. MS (m/z): 191
(M+−109 (43)), 163 (47), 121 (3), 110 (38), 101 (7), 91 (23), 77 (9), 65 (17), 43 (100). The
ee was determined to be 87% ee by HPLC (Chiralcel OJ column, hexane/i-PrOH = 90 : 10,
flow rate 1.0 mL/min, λ = 254 nm): tR(major) = 53.46 min, tR(minor) = 47.58 min. HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C17H16O3SNa 323.0712; found 323.0725.
4.3.2. 1-Oxo-1-(phenylthio)-3-(p-tolyl)propan-2-yl acetate ( 3b)
Yield 84%; white solid; mp: 53–55◦C. IR (nujol): 3024, 1754, 1699, 1217 cm−1. [α]D27 = +135.3
1
(c 0.34, CHCl3). H NMR (400 MHz, CDCl3) δ: 2.13 (s, 3H), 2.33 (s, 3H), 3.05–3.24 (m,
2H), 5.51 (dd, J = 8.0, 4.0 Hz, 1H), 7.11 (s, 4H) 7.35–7.42 (m, 5H). 13C NMR (100 MHz,
CDCl3) δ: 20.8, 21.2, 37.9, 78.8, 126.4, 129.3, 129.43, 129.48, 129.7, 132.4, 134.9, 136.8, 169.9,
196.9. MS (m/z): 205 (M+−109 (36)), 177 (46), 145 (4), 135 (10), 109 (34), 91 (11), 77 (17),
65 (11), 43 (100), 39 (7). The ee was determined to be 88% ee by HPLC (Chiralpak AD-H
column, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL/min, λ = 254 nm): tR(major) = 7.90 min,
tR(minor) = 6.65 min. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H18O3SNa 337.0869;
found 337.0883.
4.3.3. 3-(4-Methoxyphenyl)-1-oxo-1-(phenylthio)propan-2-yl acetate ( 3c)
Yield 75%; pale yellow oil. IR (neat): 2951, 1754, 1707, 1516, 1252 cm−1. [α]D24 = +120.0 (c
1
1.65, CHCl3). H NMR (500 MHz, CDCl3) δ: 2.14 (s, 3H), 3.13 (ddd, J = 20.0, 15.0, 5.0 Hz,
2H), 3.79 (s, 3H), 5.50 (dd, J = 10.0, 5.0 Hz, 1H), 6.84 (d, J = 10.0 Hz, 2H), 7.14 (d, J =
10.0 Hz, 2H), 7.36–7.42 (m, 5H). 13C NMR (125 MHz, CDCl3) δ: 20.8, 45.0, 55.3, 81.2, 114.2,
124.9, 129.2, 129.3, 130.1, 130.8, 133.6, 158.9, 169.8, 197.4. MS (m/z): 221 (M+−109 (38)),
193 (61), 179 (3), 161 (22), 151 (24), 121 (88), 109 (32), 91 (13), 77 (17), 65 (18), 43 (100), 39 (6)
.The ee was determined to be 89% ee by HPLC (Chiralpak AD-H column, hexane/i-PrOH = 90 :
10, flow rate 1.0 mL/min, λ = 254 nm): tR(major) = 12.71 min, tR(minor) = 10.14 min. (ent-
3c): Yield 90%; [α]2D4 = −86.0 (c 1.00, CHCl3). The ee was determined to be −85% ee. HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C18H18O4SNa 353.0818; found 353.0833.
4.3.4. 3-(4-Fluorophenyl)-1-oxo-1-(phenylthio)propan-2-yl acetate ( 3d)
Yield 93%; pale yellow oil. IR (neat): 2964, 1767, 1465, 1379 cm−1. [α]D26 = +125.7 (c 3.5,
1
CHCl3). H NMR (400 MHz, CDCl3) δ: 2.14 (s, 3H), 3.16 (ddd, J = 16.0, 12.0, 4.0 Hz, 2H),
5.52 (dd, J = 8.0, 4.0 Hz, 1H), 7.00 (t, J = 8.0 Hz, 2H), 7.17–7.20 (m, 2H), 7.35–7.42 (m, 5H).
13C NMR (100 MHz, CDCl3) δ: 20.7, 37.4, 78.5, 115.3, 115.5, 126.2, 129.4, 129.8, 131.11,
131.19, 134.8, 163.3, 169.7, 196.8. MS (m/z): 209 (M+−109 (53)), 181 (52), 149 (2), 121
(5), 109 (62), 101 (6), 83 (10), 65 (13), 43 (100), 39 (5). The ee was determined to be
87% ee by HPLC (Chiralpak AD-H column, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL/min,

Journal of Sulfur Chemistry 657
λ = 254 nm): tR(major) = 8.97 min, tR(minor) = 7.01 min. HRMS (ESI-TOF) m/z [M + Na]+
calcd for C17H15FO3SNa 341.0618; found 341.0627.
4.3.5. 1-Oxo-1-(phenylthio)-3-(4-(trifluoromethyl)phenyl)propan-2-yl acetate (3e)
Yield 97%; pale yellow oil. IR (neat): 375, 2930, 1759, 1699, 1328 cm−1. [α]D22 = +96.1 (c
1
0.66, CHCl3). H NMR (400 MHz, CDCl3) δ: 2.16 (s, 3H), 3.25 (ddd, J = 16.0, 12.0, 4.0 Hz,
2H), 5.58 (dd, J = 8.0, 4.0 Hz, 1H), 7.34–7.44 (m, 7H), 7.58 (d, J = 8.0 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ: 20.9, 37.9, 78.7, 127.1, 127.3, 127.4, 128.9, 129.4, 129.8, 130.0, 134.9,
140.1, 140.8, 169.9, 196.9. MS (m/z): 259 (M+−109 (28)), 231 (17), 159 (4), 110 (31), 91
(2), 65 (7), 43 (100), 39 (3). The ee was determined to be 85% ee by HPLC (Chiralpak AD-H
column, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL/min, λ = 254 nm): tR(major) = 7.79 min,
tR(minor) = 6.44 min. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H15F3O3SNa 391.0586;
found 391.0597.
4.3.6. 3-([1,1ꢁ-Biphenyl]-4-yl)-1-oxo-1-(phenylthio)propan-2-yl acetate (3f)
Yield 95% (33.9 g); white solid; mp: 117–121◦C. IR (nujol): 2960, 1764, 1716, 1465, 1371 cm−1
.
[α]2D6 = +98.1 (c 1.06, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 2.16 (s, 3H), 3.24 (ddd, J = 20.0,
16.0, 4.0 Hz, 2H), 5.58 (dd, J = 8.0, 4.0 Hz, 1H), 7.29–7.45 (m, 10H), 7.57 (dd, J = 16.0, 8.0 Hz,
4H). 13C NMR (100 MHz, CDCl3) δ: 20.9, 37.9, 78.7, 126.3, 127.1, 127.3, 127.4, 128.9, 129.4,
129.8, 130.0, 134.6, 134.9, 140.1, 140.8, 169.9, 196.9. MS (m/z): 267 (M+−109 (35)), 239 (40),
207 (8), 179 (10), 167 (72), 152 (19), 109 (32), 65 (11), 43 (100), 39 (4). The ee was determined to
be 87% ee by HPLC (Chiralpak AD-H column, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL/min,
λ = 254 nm): tR(major) = 10.52 min, tR(minor) = 8.51 min. HRMS (ESI-TOF) m/z [M + Na]+
calcd for C23H20O3SNa 399.1025; found 399.1045.
4.3.7. 1-Oxo-1-(phenylthio)-3-(m-tolyl)propan-2-yl acetate ( 3g)
Yield 97%; pale yellow oil. IR (neat): 2968, 1759, 1707, 1465, 1379 cm−1. [α]D26 = +117.5 (c
1.26, CHCl3). 1H NMR (400 MHz, CDCl3) δ: 2.13 (s, 3H), 2.34 (s, 3H), 3.21 (ddd, J = 8.0, 16.0,
20.0 Hz, 2H), 5.52 (dd, J = 8.0, 4.0 Hz, 1H), 7.02–7.08 (m, 3H), 7.18–7.21 (m, 1H), 7.36–7.41
(m, 5H). 13C NMR (100 MHz, CDCl3) δ: 20.8, 21.5, 38.2, 78.8, 126.4, 126.6, 127.9, 128.4, 129.4,
129.8, 130.3, 134.9, 135.4, 138.2, 169.9, 196.9. MS (m/z): 205 (M+−109 (68)), 177 (47), 163
(22), 135 (11), 110 (38), 91 (10), 77 (12), 65 (13), 43 (100), 39 (5). The ee was determined to be
86% ee by HPLC (Chiralpak AD-H column, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL/min,
λ = 254 nm): tR(major) = 6.70 min, tR(minor) = 5.71 min. HRMS (ESI-TOF) m/z [M + K]+
calcd for C18H18O3SK 353.0608; found 353.0622.
4.3.8. 1-Oxo-1-(phenylthio)-3-(o-tolyl)propan-2-yl acetate (3h)
Yield 94%; pale yellow oil. IR (neat): 3034, 1750, 1729, 1439, 1367, 1226 cm−1. [α]D26 = +100.0
(c 1.5, CHCl3). 1H NMR (500 MHz, CDCl3) δ: 2.10 (s, 3H), 2.37 (s, 3H), 3.20 (ddd, J = 20.0,
10.0, 5.0 Hz, 2H), 5.52 (dd, J = 10.0, 5.0, 1H), 7.15–7.17 (m, 4H), 7.38–7.42 (m, 5H). 13C
NMR (125 MHz, CDCl3) δ: 19.6, 20.7, 35.6, 78.2, 126.1, 126.4, 127.4, 129.4, 129.8, 130.3,
130.6, 134.0, 134.8, 136.8, 169.8, 196.9. MS (m/z): 205 (M+−109 (49)), 177 (36), 163 (10),
135 (8), 110 (29), 93 (5), 77 (8), 65 (8), 43 (100), 39 (4). The ee was determined to be 87%
ee by HPLC (Chiralpak AD-H column, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL/min, λ =

658 F. Capitta et al.
254 nm): tR(major) = 6.72 min, tR(minor) = 5.46 min. HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C18H18O3SNa 337.0869; found 337.0878.
Funding
Financial support from the MIUR, Rome, and by the University of Cagliari (National Project “Stereoselezione in Sintesi
Organica Metodologie ed applicazioni”), from FIRB-2008 and Sardinia Regional Government (P.O.R. Sardegna F.S.E.
Operational Programme of the Autonomous Region of Sardinia, European Social Fund 2007–2013-Axis IV Human
Resources, Objective l.3, Line of Activity l.3.1) is gratefully acknowledged.
Supplemental data
Supplemental data for this article can be accessed at 10.1080/17415993.2014.946506.
References
[1] Coppola CM, Schuster HF. α-Hydroxy acids in enantioselective synthesis. New York: Wiley-VCH; 1997.
[2] Hanessian S. Total synthesis of natural product: the chiron approach. New York: Pergamon; 1983.
[3] Xu Y, Duan X, Li M, Jiang L, Zhao G, Meng Y, Chen L. Synthesis of the key precursor of hirsutellide A. Molecules.
2005;10:259–264.
[4] Xu Y, Chen L, Duan X, Meng Y, Jiang L, Li M, Zhao G, Li Y. Total synthesis of hirsutellide A. Tetrahedron Lett.
2005;46:4377–4379.
[5] Yadav JS, Purnima KV, Subba Reddy BV, Nagaiah K, Ghamdi AK. Total synthesis of cryptophycin-24 (arenastatin
A) via Prins cyclization. Tetrahedron Lett. 2011;52:6709–6712.
[6] Sammet B, Brax M, Sewald N. A two step synthesis of a key unit B precursor of cryptophycins by asymmetric
hydrogenation. Beilstein J Org Chem. 2011;7:243–245.
[7] Borah AJ, Goswami P, Barua NC, Phukan P. Synthesis of unit-B of cryptophycin-24 via Sharpless asymmetric
dihydroxylation. Tetrahedron Lett. 2012;53:7128–7130.
[8] McCubbin JA, Maddess ML, Lautens M. A two step synthesis of a key unit B precursor of cryptophycins by
asymmetric hydrogenation. Org Lett. 2006;8:2993–2996.
[9] Barrow RA, Hemscheidt T, Liang J, Paik S, Moore RE, Tius MA. Total synthesis of cryptophycins. Revision of the
structures of cryptophycins A and C. J Am Chem Soc. 1995;117:2479–2490.
[10] Scherkenbeck J, Lüttenberg S, Ludwig M, Brücher K, Kotthaus A. Segment solid-phase total synthesis of the
anthelmintic cyclooctadepsipeptides PF1022A and emodepside. Eur J Org Chem. 2012;8:1546–1553.
[11] Hwu JR, Varadaraju TG, Abd-Elazem IS, Huang RCC. First total syntheses of oresbiusins A and B, their antipodes,
and racemates: configuration revision and anti-HIV activity. Eur J Org Chem. 2012;25:4684–4688.
[12] Fischer J, Savage GP, Coster MJ. A concise route to dihydrobenzo[b]furans: formal total synthesis of (+)-
lithospermic acid. Org Lett. 2011;13:3376–3379.
[13] Lakshminarayana N, Prasad YR, Gharat L, Thomas A, Ravikumar P, Narayanan S, Srinivasan CV, Gopalan B.
Synthesis and evaluation of some novel isochroman carboxylic acid derivatives as potential anti-diabetic agents.
Eur J Med Chem. 2009;44:3147–3157.
[14] Nestl BM, Glueck SM, Hall M, Kroutil W, Stuermer R, Hauer B, Faber K. Biocatalytic racemization of (hetero)aryl-
aliphatic α-hydroxycarboxylic acids by lactobacillus spp. proceeds via an oxidation–reduction sequence. Eur J Org
Chem. 2006;20:4573–4577.
[15] Alford BL, Hügel HM. Total synthesis of (+)-pentamethylsalvianolic acid C. Org Biomol Chem. 2013;11:
2724–2727.
[16] Zheng Z, Sheng B, Gao C, Zhang H, Qin T, Ma C, Xu P. Highly stereoselective biosynthesis of (R)-α-hydroxy
carboxylic acids through rationally re-designed mutation of D-lactate dehydrogenase. Sci Rep. 2013;3:3401.
doi:10.1038/srep03401
[17] Wang Z, La B, Fortunak JM, Meng X-J, Kabalka GW. Enantioselective synthesis of α-hydroxy carboxylic
acids: direct conversion of α-oxocarboxylic acids to enantiomerically enriched α-hydroxy carboxylic acids via
neighboring group control. Tetrahedron Lett. 1998;39:5501–5504.
[18] Carpentier J-F, Mortreux A. Asymmetric hydrogenation of α-keto acid derivatives by rhodium-{amidophosphine-
phosphinite} catalysts. Tetrahedron: Asymmetry. 1997;8:1083–1099.
[19] Linares-Palomino PJ, Surya Prakash GK, Olah GA. Trifluoromethanesulfonic acid catalyzed alkylation of arenes
with methyl (2R)-glycidate. Helv Chim Acta. 2005;88:1221–1225.
[20] Borah AJ, Goswami P, Barua NC, Phukan P. Synthesis of unit-B of cryptophycin-24 via Sharpless asymmetric
dihydroxylation. Tetrahedron Lett. 2012;53:7128–7130.
[21] Chinthapally K, Baskaran S. A chemoselective oxidation of monosubstituted ethylene glycol: facile synthesis of
optically active α-hydroxy acids. Org Biomol Chem. 2014;12:4305–4309.

Journal of Sulfur Chemistry 659
[22] Varadaraju TG, Hwu JR. Synthesis of anti-HIV lithospermic acid by two diverse strategies. Org Biomol Chem.
2012;10:5456–5465.
[23] Kunz H, Lerchen HG. Stereocontrolled synthesis of D-α-hydroxy carboxylic acids from L-amino acids. Tetrahedron
Lett. 1987;28:1873–1876.
[24] MacMillan DWC. The advent and development of organocatalysis. Nature. 2008;455:304–308.
[25] Maruoka K, editor. Science of synthesis: asymmetric organocatalysis. Stuttgart: Georg Thieme Verlag KG; 2012.
[26] Melchiorre P, Marigo M, Carlone A, Bartoli G. Asymmetric aminocatalysis – gold rush in organic chemistry. Angew
Chem Int Ed. 2008;47:6138–6171.
[27] Marcelli T, Hiemstra H. Cinchona alkaloids in asymmetric organocatalysis. Synthesis. 2010;8:1229–1279.
[28] Pellissier H. Recent developments in asymmetric organocatalytic domino reactions. Adv Synth Catal.
2012;354:237–294.
[29] Ren Q, Wang J. Recent developments in amine-catalyzed non-asymmetric transformations. Asian J Org Chem.
2013;2:542–557.
[30] Lv F, Liu S, Hu W. Recent advances in the use of chiral Brønsted acids as cooperative catalysts in cascade and
multicomponent reactions. Asian J Org Chem. 2013;2:824–836.
[31] Capitta F, Frongia A, Piras PP, Pitzanti P, Secci F. Enantioselective organocatalytic rearrangement of α-acyloxy-β-
keto sulfides to α-acyloxy thioesters. Adv Synth Catal. 2010;352:2955–2960.
[32] Schmitt E, Schiffers I, Bolm C. Organocatalytic conversion of arylglyoxals into optical active mandelic acid
derivatives. Tetrahedron Lett. 2009;50:3185–3188.
[33] Suzuki T, Honda Y, Izawa K, Williams RM. Remarkable diastereomeric rearrangement of an α-acyloxy
β-ketosulfide to an α-acyloxy thioester:? a novel approach to the synthesis of optically active (2S,3S) β-amino
α-hydroxy acids. J Org Chem. 2005;70:7317–7323.
[34] Mimoto T, Terashima K, Nojima S, Takaku H, Nakayama M, Shinthani M, Yamaoka T, Hayashi H.
Structure–activity and structure–metabolism relationships of HIV protease inhibitors containing the 3-hydroxy-
2-methylbenzoylallophenylnorstatine structure. Bioorg Med Chem. 2004;12:281–293.
[35] Akai S, Kita Y. Recent advances in Pummerer reactions. Top Curr Chem. 2007;274:35–76.
[36] Smith LHS, Coote SC, Sneddon HF, Procter DJ. Beyond the Pummerer reaction: recent developments in thionium
ion chemistry. Angew Chem Int Ed. 2010;49:5832–5844.
[37] Mohr JT, Hong AY, Stoltz BM. Enantioselective protonation. Nat Chem. 2009;1:359–369.
[38] Duhamel L, Duhamel P, Plaquevent JC. Enantioselective protonations: fundamental insights and new concepts.
Tetrahedron: Asymmetry. 2004;15:3653–3691.
[39] Claraz A, Oudeyer S, Levacher V. Deracemization of α-substituted carbonyl compounds via catalytic enantioselec-
tive protonation of their corresponding enolates. Curr Org Chem. 2012;16:2192–2205.
[40] Poisson T, Oudeyer S, Brière J-F, Levacher V. Organocatalyzed enantioselective protonation. In: Mahrwald R,
editor. Enantioselective organocatalyzed reactions I. 1st ed. Berlin: Springer; 2011. p. 67.
[41] Frongia A, Melis N, Secci F. Organocatalyzed tandem process involving asymmetric protonations as a stereo-
defining step. C R Chim. 2014. doi:10.1016/j.crci.2014.05.002
[42] Oudeyer S, Brière J-F, Levacher V. Progress in catalytic asymmetric protonation. Eur J Org Chem. 2014.
doi:10.1002/ejoc.201402213.
[43] Capitta F, Frongia A, Piras PP, Pitzanti P, Secci F. Organocatalytic asymmetric tandem condensation–intramolecular
rearrangement–protonation: an approach to optically active α-amino thioester derivatives. Org Biomol Chem.
2012;10:490–494.
[44] Frongia A, Secci F, Capitta F, Piras PP, Sanna ML. Catalytic enantioselective Amadori–Heyns rearrangement of
racemic α-hydroxy ketones with arylamines: synthesis of optically active α-arylamino ketones. Chem Commun.
2013;49:8812–8814.
[45] Aitken DJ, Caboni P, Eijsberg H, Frongia A, Guillot R, Ollivier J, Piras PP, Secci F. Catalytic enantioselective
synthesis of α-arylaminocyclobutanones. Adv Synth Catal. 2014;356:941–945.
[46] Frongia A, Melis N, Serra I, Secci F, Piras PP, Caboni P. Organocatalytic asymmetric condensation/keto–enol
tautomerization tandem reaction: access to cyclobutanone α-amino acid ester derivatives. Asian J Org Chem.
2014;3:378–381.
[47] Shie J-J, Fang J-M, Kuo T-H, Kuo C-J, Liang P-H, Huang H-J, Wu Y-T, Jan J-T, Cheng Y-SE, Wong C-H. Inhibition
of the severe acute respiratory syndrome 3CL protease by peptidomimetic α,β-unsaturated esters. Bioorg Med
Chem. 2005;13:5240–5252.
[48] Li S, Zhu S-F, Xie J-H, Song S, Zhang C-M, Zhou Q-L. Enantioselective hydrogenation of α-aryloxy and α-alkoxy
α,β-unsaturated carboxylic acids catalyzed by chiral spiro iridium/phosphino-oxazoline complexes. J Am Chem
Soc. 2010;132:1172–1179.
[49] Dragovich PS, Prins TJ, Zhou R, Webber SE, Marakovits JT, Fuhrman SA, Patick AK, Matthews DA, Lee CA,
Ford CE, Burke BJ, Rejto PA, Hendrickson TF, Tuntland T, Brown EL, Meador III JW, Ferre RA, Harr JEV,
Kosa MB, Worland ST. Structure-based design, synthesis, and biological evaluation of irreversible human rhi-
novirus 3C protease inhibitors. 4. Incorporation of P1 lactam moieties as l-glutamine replacements. J Med Chem.
1999;42:1213–1224.
[50] Applegate GA, Cheloha W, Nelson DL, Berkowitz DB. A new dehydrogenase from clostridium acetobutylicum
for asymmetric synthesis: dynamic reductive kinetic resolution entry into the Taxotère side chain. Chem Commun.
2011;47:2420–2422.
[51] Wang P, Tao W-J, Sun X-L, Liao S, Tang Y. A highly efficient and enantioselective intramolecular Cannizzaro
reaction under TOX/Cu(II) catalysis. J Am Chem Soc. 2013;135:16849–16852.

660 F. Capitta et al.
[52] Alamsetti SK, Sekar G. Chiral cobalt-catalyzed enantioselective aerobic oxidation of α-hydroxy esters. Chem
Commun. 2010;46:7235–7237.
[53] Wang W, Liu X, Lin L, Feng X. Recent progress in the chemically catalyzed enantioselective synthesis of
cyanohydrins. Eur J Org Chem. 2010:4751–4759.
[54] Zhu L, Meng Q, Fan W, Xie X, Zhang Z. Direct asymmetric hydrogenation of 2-oxo-4-arylbut-3-enoic acids. J Org
Chem. 2010;75:6027–6030.
[55] Enders D, Stöckel BA, Rembiak A. Enantio- and chemoselective Brønsted-acid/Mg(nBu)2 catalysed reduction of
α-keto esters with catecholborane. Chem Commun. 2014;50:4489–4491.