Bifunctional Thiourea-Catalyzed Stereoablative Retro-Sulfa-Michael Reaction: Concise and Diastereoselective Access to Chiral 2,4-Diarylthietanes

Article abstract of DOI:10.1055/s-0036-1588612

Owing to the chiral recognition capacity of bifunctional thioureas, a stereoablative retro-sulfa-Michael reaction has been developed. Utilization of a biphasic system enabled us to render the process catalytic. The usefulness of this methodology was further illustrated by the diastereoselective synthesis of all possible stereoisomers of 2,4-diarylthiethanes.

Full text of DOI:10.1055/s-0036-1588612

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–K
paper
A
A. Bacsó et al.
Paper
Synthesis
Bifunctional Thiourea-Catalyzed Stereoablative Retro-Sulfa-
Michael Reaction: Concise and Diastereoselective Access to Chiral
2,4-Diarylthietanes
András Bacsó
O
Ar2
Ar2
OEt
OEt
Mariann Szigeti
Szilárd Varga
Tibor Soós*
P
S
S
S
S
O
S
O
P
O
O
OEt
OEt
Ar1
Ar1
Ar2
Ar1
Ar1
Ar2
O
Ar1
Ar1
cat.
ent-cat.
O
S
Ar1
Ar1
Ar2
Ar2
Ar1
Ar2
OEt
P
O
S
OEt
Institute of Organic Chemistry, Research Centre for Natural
Sciences, Magyar tudósok körútja 2A, 1117 Budapest,
Hungary
racemic
Ar2
Ar2
soos.tibor@ttk.mta.hu
Dedicated to Professor Dieter Enders on the occasion of his
70th birthday
Received: 06.09.2016
Accepted: 09.09.2016
Published online: 14.10.2016
DOI: 10.1055/s-0036-1588612; Art ID: ss-2016-z0614-op
thiourea catalysts. Furthermore, the synthetic utility of this
chiral protocol was demonstrated via developing a concise
and diastereoselective synthesis of 2,4-diarylthietanes.
Abstract Owing to the chiral recognition capacity of bifunctional
thioureas, a stereoablative retro-sulfa-Michael reaction has been devel-
oped. Utilization of a biphasic system enabled us to render the process
catalytic. The usefulness of this methodology was further illustrated by
the diastereoselective synthesis of all possible stereoisomers of 2,4-di-
arylthiethanes.
OMe
OMe
N
H
H
N
N
NH
HN
N
S
NH
Ar
HN
Ar
S
Key words organocatalysis, bifunctional, thiourea, stereoablative,
sulfa-Michael
1a
1b
Ar = 3,5-(CF3)2C6H3
O
O
Nu
1a
a
+
H
Nu
Over the last decade, the enantioselective organocataly-
sis has been evolved into a viable synthetic methodology
for the synthesis of chiral molecules having even multiple
chiral centers.1 One of the archetypal catalysts is the
thiourea-based bifunctional organocatalyst that has unique
capacity to activate and organize the substrates via oxyan-
ion-hole-like hydrogen bond network.2 Since the inception
of the bifunctional thiourea or squaramide organocatalysis,
the primary focus has been to explore the catalytic conver-
sion of achiral molecules into chiral ones (Scheme 1, a).3 Ac-
cordingly, the transformation of chiral substrates in bifunc-
tional non-covalent organocatalysis, even as a chiral inter-
mediate of an organocascade reaction, has been
comparatively scant. Among these reactions, one could
identify a still rather rare, but distinct class of strategic ap-
proach, the enantioselective stereoablative reactions.4
These processes deliver enantioenriched compounds via
destroying stereogenic elements.5,6 Despite being complexi-
ty reduction method, there can be several practical advan-
tages that merit further exploration. Herein, we describe
the development of a catalytic stereoablative retro-sulfa-
Michael reaction that was promoted by bifunctional
R1
R2
R1
R2
ee up to 99%
OH
O
R1
NO2
R2 R3
1a
O
O
b
R3
R2
O
R1
CHO
CHO
NO2
OH
NO2
R1
1b
R3
R1
R2
R3
R2
NO2
dr up to 99:1
Scheme 1 (a) Different application of organocatalysts: conventional
bifunctional catalysis; (b) double diastereocontrol in iterative reactions
As the bifunctional non-covalent organocatalytic pro-
cesses afford or proceed through chiral molecules, the im-
portance and reactivity consequence of double diastereo-
control should also be taken into account for methodology
design and development. For example, we have found a lim-
iting case for organocascade reaction that was the result of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

B
A. Bacsó et al.
Paper
Synthesis
the exaggerated form of the double diastereocontrol
(Scheme 1, b). Accordingly, the chiral product of the first or-
ganocatalytic Michael addition precluded its own further
reactions owing to an extreme form of the mismatched cat-
alyst-substrate combination. This mismatch limitation
could be alleviated and thus an iterative sequence was de-
veloped by the sequential application of both enantiomers
of the organocatalyst [Scheme 1 (b), 1a and 1b].7 Moreover,
our recent kinetic investigation of a bifunctional squara-
mide-promoted Michael addition revealed that the bifunc-
tional squaramide organocatalyst (e.g., 1f) could promote a
stereoablative process as it cleaved the C–C bond stereose-
lectively in a stoichiometric retro-Michael reaction.8 These
findings indicate that bifunctional non-covalent organocat-
alysts do have a chiral recognition capability that could be
synthetically exploited. Encouraged by the retro-Michael
power of bifunctional organocatalyst, we became interest-
ed to apply catalytic stereoablative reaction for challenging
substrates.
air-exposed condition.9 Additionally, phosphorothioic acids
can be easily prepared from the corresponding dialkyl
phosphites on multigram scale.9e,10 However, there is no
asymmetric catalytic sulfa-Michael processes11 of phospho-
rothioic acids. The lack of viable chiral synthetic method
might be the result of the enhanced reactivity of dialkyl-
phosphorothioic acids. For example, diethylphosphorothio-
ic acid (2a) reacted spontaneously and rapidly with chal-
cone (3a) at room temperature to afford racemic Michael
adduct 4a (R1 = R2 = Ph) (Scheme 2). Applications of catalyt-
ic amount of chiral organocatalysts 1a–g in this reaction,
however, had no beneficial effect on yields, reaction times
and most importantly, practically no chiral inductions were
observed. These findings revealed a significant limitation
for the direct asymmetric methodology of phosphorothioic
acid 2a; nevertheless, we speculated that a stereoablative
approach, as a complementary approach, might bypass this
synthetic limitation.
Accordingly, we added catalytic amount of bifunctional
thiourea 1c to the toluene solution of racemic Michael
adduct 4a. To our delight, the bifunctional thiourea 1c could
initiate a stereoselective retro-Michael reaction affording
enantiomerically enriched adduct 4a. As the enantiomeric
The dialkylphosphorothioic acids are unique sulfur nuc-
leophiles that can be used as safer alternatives of H2S in or-
ganic synthesis. Their clear practical advantages over the
common thiol reagents are being odorless and stable under
a) The sulfa-Michael reaction
O
O
SP(O)(OEt)2
R2
O
+
O
P
R1
R2
HS
R1
O
2a
4
3
39–79% isolated yield
b) Catalysts
R
CF3
F3C
O
N
N
CF3
O
N
H
O
N
H
N
H
F3C
N
N
H
CF3
NH
S
O
CF3
NH
NH
Si
CF3
NH
S
N
H
CF3
O
1c R = CH2CH3
1a R = CH=CH2
1e R = C≡CH
1f
1d
1g
c) The catalytic retro-Michael reaction
O
O
SP(O)(OEt)2
R2
+
R1
R2
R1
ee up to 95%
organic
phase
O
SP(O)(OEt)2
R2
R1
aqueous
phase
H-1c
SP(O)(OEt)2
+
2
base
1c
Scheme 2 (a) The sulfa-Michael reaction to synthesize the racemic adduct; (b) the tested catalysts, and (c) the concept of the two-phase system to
carry out the catalytic stereoablative reaction
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

C
A. Bacsó et al.
Paper
Synthesis
excess was proportional to the catalyst loading, we as-
sumed that the Michael adduct 4a underwent a stoichio-
metric retro-Michael reaction by the bifunctional thiourea
1c and the released phosphorothioic acid 2a formed a cata-
lytically inactive salt with 1c. To turn the reaction into cata-
lytic, the catalyst should be liberated from its phosphoro-
thioic salt without impairing the retro-Michael procedure.
To solve this challenge, we envisioned a biphasic reaction
system in which the retro-Michael reaction would occur in
the organic phase, and the catalyst would be regenerated
from its salt in the aqueous phase by an inorganic base
(Scheme 2, c).
action temperature (entries 10–18), catalyst and base load-
ing allowed to identify an optimal parameters for this reac-
tion [10 mol% catalyst 1c, r.t., toluene/aqueous NaHCO3
(0.55 equiv)].
Table 1 Optimization for the Retro-Michael Reaction of 4a
O
O
OEt
OEt
P
P
O
S
O
S
OEt
OEt
1c (0.10 equiv)
NaHCO3 (0.55 equiv)
+
toluene, r.t., 24 h
4a
racemic
(+)-4a, yield: 40%, ee: 94%
Thus, we started to explore the feasibility of biphasic
catalytic stereoablation of the racemic 4a (Table 1). First,
the biphasic retro-Michael reaction was probed without or-
ganocatalyst and it was found that no reaction occurred as
no formation of chalcone (3a) was observed (Table1, entry
1). This control experiment highlighted that such an inor-
ganic base as NaHCO3 was not able to trigger a retro-
Michael reaction alone. Next, different bifunctional organo-
catalysts were examined at 10 mol% loading in biphasic tol-
uene/aqueous NaHCO3 settings. Gratifyingly, good enantio-
selectivity was achieved with catalyst 1c demonstrating
that the stereoablation can be rendered catalytic. Investiga-
tion of the less basic variants of 1c, 1a, and 1e, revealed that
catalysts possessing less basic site deliver the Michael ad-
duct 4a in significantly lower enantioselectivities (entries 2,
3). As 1b, the pseudoenantiomer of 1a provided the oppo-
site enantiomeric Michael adduct 4a with a rather medio-
cre enantioselectivity, its simplified structural analogue,
the Takemoto catalyst 1d was probed. Notably, the Takemoto’s
catalyst furnished the Michael adduct with markedly higher
stereoselectivity (entries 4, 5). As the double hydrogen do-
nor motifs of bifunctional organocatalysts occupy a privi-
leged place in organocatalytic methodology development, a
squaramide based bifunctional organocatalysts 1f was also
investigated. Compared to its thiourea congener 1a, catalyst
1f was less enantiospecific (entry 6), thus the enhancement
of the Lewis acidity of the organocatalyst resulted in a re-
duced catalytic performance. Finally, prolinol based
Jørgensen’s catalyst 1g was investigated and found to be an
active promoter. However, this monofunctional secondary
amine catalyst was not able to induce enantioselectivity
(entry 7). In subsequent experiments the effect of the ap-
plied base was studied. It was found that the enantioselec-
tivities were irrespective if stronger inorganic base was
used (entry 8 vs 10).12 Replacing of the inorganic base with
an organic one would further simplify the procedure. How-
ever, this monophasic reaction afforded the Michael adduct
with low stereoselectivity (entry 9). The enantioselectivity
of the retro-Michael reaction was found to be barely depen-
dent on the choice of solvent, the increase in polarity re-
duced only slightly the enantiomeric excess (entries 12,
13). Further optimization of the reaction conditions on re-
enantioenriched
Entry
Deviation from the above conditions
Yield (%)a
ee (%)
1
2
0.50 equiv NaHCO3, no catalyst
0.50 equiv NaHCO3, 1a
0.50 equiv NaHCO3, 1e
0.50 equiv NaHCO3, 1b
0.50 equiv NaHCO3, 1d
0.50 equiv NaHCO3, 1f
0.50 equiv NaHCO3, 1g
0.50 equiv Na2CO3
0.5 Et3N
93
48
43
44
39
43
63
41
38
42
37
40
39
40
27
49
39
7
0
63
56
36*
78*
59
0
3
4
5
6
7
8
82
28
84
98
74
81
85
99
71
89
90
73
9
10
11
12
13
14
15
16
17
18
19
0.50 equiv NaHCO3
0.60 equiv NaHCO3
CH2Cl2
EtOAc
0.05 equiv 1c
0.20 equiv 1c
9 °C
50 °C
90 °C
6 h
44
a Isolated yields for the enantioenriched Michael adduct.
* Indicates where the opposite enantiomer was preferred.
With this optimal catalytic condition in hand, we next
sought to examine the scope and limitations of the ste-
reoablative transformation. As shown in Scheme 3, a range
of structurally diverse chalcone derivatives, including elec-
tron-withdrawing and electron-donating groups, undergo
stereoablative retro-Michael reaction with high enantiose-
lectivity. The nitro-chalcone derivatives 4h and 4i gave
lower enantioselectivites that might be the result of their
poor solubility in toluene. Pleasingly, pyrrole derivative 4o
proved to be also a competent reaction partner in the ste-
reoablative reaction. This result is of a particular note as N-
acylpyrroles are easily accessible compounds that function
as an ester surrogate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

D
A. Bacsó et al.
Paper
Synthesis
O
P
1c (0.10 equiv)
O
OR3
OR3
OR3
O
P
NaHCO3 (0.55 equiv)
O
P
OR3
OR3
O
S
O
S
+
+
OR3
toluene, r.t., 24 h
R1
R2
HS
R1
R2
R1
R2
racemic
enantioenriched
O
O
S
O
O
O
O
OEt
OEt
OEt
OEt
OEt
OEt
P
P
P
P
P
P
O
S
O
O
S
O
S
O
S
O
S
OEt
OEt
OEt
OEt
OEt
OEt
Ph
Ph
Ph
Ph
Ph
Ph
Cl
Cl
O
O
(+)-4b, 39%a, ee: 93%b
(+)-4c, 40%, ee: 90%
conv.: 60%, S = 11.8
(+)-4d, 42%, ee: 82%
conv.: 58%, S = 9.3
(+)-4e, 37%, ee: 86%
conv.: 63%, S = 7.8
(+)-4f, 49%, ee: 66%
conv.: 51%, S = 5.6
(+)-4g, 39%, ee: 82%
conv.: 61%, S = 8.0
conv.: 61%c, S = 12.3d
O
P
O
O
O
O
O
OEt
OEt
OEt
OEt
OEt
OEt
P
P
P
P
P
O
S
O
S
O
S
O
S
O
S
O
S
OEt
OEt
OEt
OEt
OEt
OEt
Ph
Ph
Ph
Ph
NO2
NO2
F
Cl
Cl
O
O
(+)-4h, 38%, ee: 78%
conv.: 62%, S = 6.3
(+)-4i, 30%, ee: 67%
conv.: 70%, S = 3.3
(+)-4j, 36%, ee: 97%
conv.: 64%, S = 13.2
(+)-4k, 36%, ee: 86%
conv.: 64%, S = 7.6
(+)-4l, 28%, ee: 86%
conv.: 72%, S = 5.0
(+)-4m, 42%, ee: 75%
conv.: 58%, S = 7.2
O
O
O
O
OEt
OEt
OEt
OEt
O
O
P
P
P
P
OEt
OEt
O
S
O
S
O
S
O
S
P
P
OEt
OEt
OEt
OEt
O
S
O
S
OEt
OEt
O
O
Ph
Ph
N
Ph
Ph
Ph
(+)-4n, 31%, ee: 87%
conv.: 69%, S = 5.8
(+)-4o, 28%, ee: 93%
conv.: 72%, S = 6.3
(+)-4p, 40%, ee: 10%
conv.: 60%, S = 1.2
(+)-4q, 42%, ee: 30%
conv.: 58%, S = 2.0
(+)-4r, 49%, ee: 21%
conv.: 51%, S = 1.8
(+)-4s, 53%, ee: 29%
conv.: 47%, S = 2.6
O
O
O
O
O
OEt
P
OEt
OPh
OPh
OPh
OPh
OPh
OPh
OPh
P
P
P
P
O
S
O
S
O
S
O
S
O
S
OPh
(+)-5b, 76%, ee: 3%
conv.: 24%, S = 1.2
(+)-5c, 80%, ee: <1%
conv.: 20%
(+)-5d, 44%, ee: 7%
conv.: 56%, S = 1.2
(+)-4t, 50%, ee: 14%
conv.: 50%, S = 1.5
(+)-5a, 38%, ee: 49%
conv.: 62%, S = 1.8
Scheme 3 Scope of the stereoablative retro-Michael-reaction. a Isolated yields for the enantioenriched Michael adduct. b Enantioselectivity was deter-
mined from chiral HPLC measurements. c Conversion % for the starting racemic compound. d Selectivity factor.13
Extensive efforts were also spent to extend this meth-
odology toward substrates 4p–t having aliphatic groups.
We found that there may be a structural prerequisite for ef-
ficient stereoablative reaction as alkyl-substituted unsatu-
rated ketones delivered the sulfa-Michael adducts only in
poor enantioselectivities. Beside appropriate electronic pa-
rameters, we postulated that π–π interaction is necessary
for high asymmetric induction. After recognizing the bene-
ficial effect of π–π interaction, substrates derived from di-
phenylphosphorothioic acid (2b) was employed, however,
this modification decreased the efficiency of the reaction as
exemplified in the reaction of 5a–d in Scheme 3.
The direct consequence of the above stereoablative
strategy is that the racemic Michael adduct is converted
back into the chalcones. Nevertheless, the inherent limita-
tion of 50% yield of this kinetic resolution process can be
overcome by recycling of chalcones.
tion of any intermediates. It started with stereoselective
CBS (Corey–Bakshi–Shibata) reduction14 of the carbonyl
moiety followed by the ring closing reaction. As the catalyst
control predominated in the catalytic CBS reduction of chi-
ral sulfa-Michael adduct 4e, diastereomerically enriched
thietanes 6a–d could be synthesized. Accordingly, all four
possible stereoisomers could be easily accessed by this mul-
tistep process.
In conclusion, we have developed an organocatalytic
stereoablative process for the retro-Michael reaction of
O,O′-dialkyl S-(3-oxo-1,3-diarylpropyl) phosphorothioates.
This is the first reported organocatalytic stereoablative pro-
cess of bifunctional thiourea-based organocatalysts. This
stereoablative procedure combined with CBS-reduction
provides a unique opportunity to synthesize 2,4-diarylthie-
tanes diastereoselectively.
In order to further demonstrate the utility of chiral
sulfa-Michael adducts and the stereoablative procedure
that deliver them, the diastereoselective synthesis of all
possible stereoisomers of 2,4-diaryl-substituted thietanes
was attempted as shown in Scheme 4. We envisioned a
multistep process performed in one pot without the isola-
All the chemicals employed are commercially available and were used
without further purification. NMR spectra were acquired at 30 °C on a
Varian 500 Inova spectrometer, running at 500, 125, and 202 MHz for
1H, 13C, and 31P, respectively. Chemical shifts (δ) are reported in ppm
relative to residual solvent signals (CHCl3, 7.26 ppm for 1H NMR,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

E
A. Bacsó et al.
Paper
Synthesis
O
OEt
P
F3C
CF3
CF3
O
S
OEt
Ph
rac-4e
Cl
OH
CF3
1c
1d
NH
1h
O
O
OEt
OEt
P
P
O
S
O
S
OEt
OEt
Ph
Ph
(–)-4e
(+)-4e
Cl
Cl
1h
ent-1h
1h
ent-1h
BH3·SMe3
BH3·SMe3
BH3·SMe3
BH3·SMe3
O
O
P
O
P
O
OEt
OEt
OEt
OEt
OEt
OEt
P
P
OH
S
OH
S
OH
S
OH
S
OEt
OEt
Ph
Cl
Ph
Ph
Cl
Ph
Cl
Cl
Cl
NaH
NaH
NaH
NaH
Cl
Cl
Cl
S
S
S
S
(S)
(R)
Ph
Ph
Ph
Ph
cis-6
yield: 36%
dr: 17:1, ee: >99%
trans-6
yield: 35%
dr: 22:1, ee: >99%
trans-ent-6
yield: 20%
dr: 10:1, ee: 99%
cis-ent-6
yield: 25%
dr: 8:1, ee: >99%
Scheme 4 Stereoselective synthesis of the four possible thietane ring
CDCl3, 77.0 ppm for 13C NMR). Standard abbreviations are used to in-
1H NMR (500 MHz, CDCl3): δ = 6.72 (br s, 1 H), 4.07 (q, J = 7.7 Hz, 2 H),
1.34 (t, J = 6.9 Hz, 3 H).
1
dicate the multiplicity in H NMR spectra. 13C NMR spectra were ac-
quired on a broad band decoupled mode. High-resolution mass spec-
trometric measurements were performed using a Q-TOF Premier
mass spectrometer (Waters Corporation, Milford, MA, USA) in positive
electrospray ionization mode. Na+ ion adduct has been measured.
Melting points are measured with SRS Optimelt apparatus. Specific
optical rotations were measured on a JASCO P-2000 automatic po-
larimeter and are expressed as degrees cm3 dm–1 g–1 at a concentra-
tion (c) of g/mL. The enantiomeric excess (ee) of the products was de-
termined by chiral stationary phase HPLC (Daicel Chiralpak AD/IB/IC
columns). The products were purified on TELEDYNE ISCO CombiFlash
Rf 200.
13C NMR (125 MHz, CDCl3): δ = 64.1 (d), 15.8 (d).
31P NMR (202 MHz, CDCl3): δ = 58.7.
The analytical data are consistent with the reported data.
O,O′-Diphenyl S-Hydrogen Phosphorothioate (2b)
To a suspension of diphenyl phosphite (11.7 g, 0.050 mol) and solid
sulfur (1.8 g, 0.055 mol) in Et2O (35 mL) in a two-necked round-bot-
tomed flask equipped with a magnetic stirrer, reflux condenser, and a
dropping funnel was slowly added Et3N (7.7 g, 0.055 mol). During the
addition of the base, the stirred mixture was allowed to warm up to
reflux and a white solid started to precipitate. After stirring for 3 h,
the mixture cooled down to r.t. Et2O (100 mL) and aq 1 M HCl
(100 mL) were added. The white solid dissolved and the organic
phase was separated. The aqueous phase was extracted again with
Et2O (50 mL) and the combined organic phases were washed with
brine, dried (Na2SO4), and concentrated under reduced pressure. The
resulting suspension was filtered over a small cotton plug to give 2b
as a yellow oil; yield: 10.5 g (79%).
O,O′-Diethyl S-Hydrogen Phosphorothioate (2a)
Na (4.6 g, 0.2 mol) was dissolved in absolute EtOH (60 mL), then Et2O
(60 mL) was added, and the solution was stirred for 1 h at r.t. Then di-
ethyl phosphite (26 mL, 0.2 mol) was added, and the stirring was con-
tinued for another 1 h. Sulfur (8.0 g, 0.25 mol) was added in portions
over 1 h and the reaction mixture was stirred overnight. Excess of sul-
fur was filtered off on a Celite pad, and the filtrate was concentrated.
H2O (10 mL) was added to the white residue and then concd HCl
(50 mL) was added at 0 °C. The aqueous phase was extracted with
Et2O (3 × 50 mL), the combined organic phases were washed with H2O
(20 mL) and brine (20 mL). After drying (Na2SO4) and concentration
on a rotary evaporator, the title compound was obtained as a light
yellow oil; yield: 26.2 g (77%).
1H NMR (500 MHz, DMSO-d6): δ = 10.80 (br s, 1 H), 7.36 (t, J = 7.8 Hz,
1 H), 7.20 (d, J = 8.3 Hz, 2 H), 7.16 (t, J = 7.3 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 151.7, 130.0, 125.0, 121.3.
31P NMR (202 MHz, CDCl3): δ = 51.4.
The analytical data are consistent with the reported data.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

F
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Synthesis
O,O′-Diethyl S-(3-Oxo-1,3-diphenylpropyl) Phosphorothioate (4a)
phase of the crude reaction mixture was purified by column chroma-
tography (Biotage® KP-Sil 10 g, hexanes/EtOAc, 9:1; to regenerate
chalcone 1:1 eluent was used).
The (E)-chalcone (3a; 833 mg, 4 mmol) was dissolved in O,O′-diethyl
S-hydrogen phosphorothioate (2a; 1.65 mL, 12 mmol). The mixture
was stirred for 2 days. The starting material and the excess of the re-
agent were separated by column chromatography (Biotage® KP-Sil
50 g, hexanes/EtOAc, 9:1; for the starting material 1:1 eluent was ap-
plied). The title compound was obtained as a light yellow oil, but after
triturating with distilled H2O it became a white crystalline solid. The
O,O′-Diethyl S-(3-Oxo-1,3-diphenylpropyl) Phosphorothioate (4a)
25
Stereoablative reaction: yield: 79 mg (40%); ee
+101.9 (c = 0.01, CHCl3).
= 94%; [α]D
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
5.1 min, tR (minor) = 4.5 min.
1
product purity was measured by H NMR spectroscopy; yield: 1.06 g
(70%); mp 70–71 °C.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 7.3 Hz, 2 H), 7.55 (t, J =
7.4 Hz, 1 H), 7.44 (m, 4 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.22 (t, J = 7.3 Hz, 1
H), 5.02–4.91 (m, 1 H), 4.15–3.95 (m, 3 H), 3.87 (dd, J = 17.1, 6.5 Hz, 1
H), 3.81–3.70 (m, 1 H), 3.66 (ddd, J = 17.1, 8.0, 1.1 Hz, 1 H), 1.29 (t, J =
7.1 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 196.0, 141.7, 136.5, 133.3, 128.7,
128.6, 128.1, 127.7, 127.6, 63.6, 63.4, 46.3, 45.5, 15.9, 15.7.
O,O′-Diethyl S-[3-Oxo-1-phenyl-3-(p-tolyl)propyl] Phosphorothio-
ate (4b)
Yield: 1.246 g (79%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.82 (d, J = 8.1 Hz, 2 H), 7.42 (d, J = 7.7
Hz, 2 H), 7.29 (t, J = 7.6 Hz, 2 H), 7.25–7.19 (m, 3 H), 4.99–4.91 (m, 1
H), 4.12–3.96 (m, 3 H), 3.82 (dd, J = 17.0, 6.6 Hz, 1 H), 3.78–3.70 (m, 1
H), 3.62 (dd, J = 17.0, 8.0 Hz, 1 H), 2.39 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H),
1.13 (t, J = 7.1 Hz, 3 H).
HRMS-EI: m/z calcd for C19H23O4PSNa [M + Na]+: 401.0952; found:
401.0952.
13C NMR (125 MHz, CDCl3): δ = 195.6, 144.2, 141.7, 134.1, 129.3,
128.5, 128.2, 127.7, 63.6, 63.4, 46.1, 45.6, 21.6, 15.9, 15.7.
HRMS-EI: m/z calcd for C20H25O4PSNa [M + Na]+: 415.1109; found:
O,O′-Diphenyl S-(3-Oxo-1,3-diphenylpropyl) Phosphorothioate
(5a)
The (E)-chalcone (3a; 833 mg, 4 mmol) was dissolved in O,O′-diphe-
nyl S-hydrogen phosphorothioate (2b; 3.20 g, 12 mmol). The mixture
was stirred for 3 days. The starting material and the excess of the re-
agent were separated by column chromatography (Biotage® KP-Sil
50 g, hexanes/EtOAc, 9:1; for the starting material 1:1 eluent was ap-
plied). The title compound was obtained as white solid after evapo-
rating the solvent. Recrystallization from EtOAc gave white needle
like crystals. The product purity was measured by 1H NMR spectros-
copy; yield: 789 mg (42%); mp 106–107 °C.
1H NMR (500 MHz, CDCl3): δ = 7.83 (d, J = 7.1 Hz, 2 H), 7.53 (t, J = 7.0
Hz, 1 H), 7.41 (t, J = 6.9 Hz, 2 H), 7.37–7.10 (m, 15 H), 5.24–5.10 (m, 1
H), 3.81 (dd, J = 17.0, 3.2 Hz, 1 H), 3.71 (dd, J = 17.0, 9.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 195.7, 150.1, 140.4, 136.3, 133.3,
129.7, 128.6, 128.1, 127.9, 127.7, 125.5, 120.8, 46.7, 46.2.
415.1111.
Stereoablative reaction: yield: 81 mg (39%); ee = 93%; [α]D25 +95.2 (c
= 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
5.1 min, tR (minor) = 4.6 min.
O,O′-Diethyl S-[3-Oxo-3-phenyl-1-(p-tolyl)propyl] Phosphorothio-
ate (4c)
Yield: 1.146 g (75%); white crystals; mp 106 °C.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 7.2 Hz, 2 H), 7.55 (t, J = 7.4
Hz, 1 H), 7.44 (t, J = 7.7 Hz, 2 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.10 (d, J = 7.8
Hz, 2 H), 4.98–4.90 (m, 1 H), 4.14–3.98 (m, 3 H), 3.86 (dd, J = 17.0, 6.3
Hz, 1 H), 3.83–3.75 (m, 1 H), 3.65 (ddd, J = 17.0, 8.3, 1.1 Hz, 1 H), 2.30
(s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.16 (t, J = 7.1 Hz, 3 H).
HRMS-EI: m/z calcd for C27H23O4PSNa [M + Na]+: 497.0952; found:
497.0942.
13C NMR (125 MHz, CDCl3): δ = 196.1, 138.4, 137.5, 136.5, 133.3,
O,O′-Diethyl/Diphenyl S-(3-Oxo-1,3-diarylpropyl) Phosphorothio-
ates from Chalcone Derivatives in Michael Addition; General Pro-
cedure
129.2, 128.6, 128.1, 127.5, 63.7, 63.5, 46.4, 45.4, 21.0, 15.9, 15.7.
HRMS-EI: m/z calcd for C20H25O4PSNa [M + Na]+: 415.1109; found:
415.1108.
The (E)-chalcone derivative 3 (4 mmol) was dissolved in O,O′-dieth-
yl/O,O′-diphenyl S-hydrogen phosphorothioate (2a/2b; 12 mmol).
The mixture was stirred for 2 days. The starting material and the ex-
cess of the reagent were separated by column chromatography (Bio-
tage® KP-Sil 50 g, hexanes/EtOAc, 9:1; for the starting material, and
1:1 for the product). The title compound was obtained as an oil, but in
some cases after triturating with distilled H2O it became a crystalline
solid.
Stereoablative reaction: yield: 83 mg (40%); ee = 90%; [α]D25 +96.2 (c
= 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 2% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
10.2 min, tR (minor) = 9.4 min.
O,O′-Diethyl S-[3-(4-Chlorophenyl)-3-oxo-1-phenylpropyl] Phos-
phorothioate (4d)
Yield: 1.321 g (80%); yellow oil.
Stereoablative Reaction; General Procedure
A vial equipped with a magnetic stirring bar was charged with the
1H NMR (500 MHz, CDCl3): δ = 7.85 (d, J = 8.6 Hz, 2 H), 7.40 (d, J = 8.1
Hz, 4 H), 7.29 (t, J = 7.5 Hz, 2 H), 7.22 (t, J = 7.3 Hz, 1 H), 4.98–4.89 (m,
1 H), 4.12–3.95 (m, 3 H), 3.86 (dd, J = 17.0, 6.4 Hz, 1 H), 3.82–3.73 (m,
1 H), 3.61 (dd, J = 17.0, 8.1 Hz, 1 H), 1.28 (t, J = 6.9 Hz, 3 H), 1.14 (t, J =
7.1 Hz, 3 H).
corresponding Michael adduct
4 (0.53 mmol) and catalyst 1c
(0.053 mmol, 10 mol%). The mixture was dissolved in toluene (1 mL),
stirred for 1 min, and then aq 0.29 M NaHCO3 solution was added
(1 mL). The mixture was stirred vigorously at r.t. for 24 h. The organic
13C NMR (125 MHz, CDCl3): δ = 194.9, 141.3, 139.8, 134.8, 129.5,
129.0, 128.6, 127.8, 127.6, 63.7, 63.6, 46.2, 45.4, 15.9, 15.7.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

G
A. Bacsó et al.
Paper
Synthesis
HRMS-EI: m/z calcd for C19H22ClO4PSNa [M + Na]+: 435.0563; found:
Stereoablative reaction: yield: 79 mg (39%); ee = 82%; [α]D25 –1.1 (c =
435.0548.
0.01, CHCl3).
25
Stereoablative reaction: yield: 91 mg (42%); ee = 82%; [α]D +68.9
(c = 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 2% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
9.7 min, tR (minor) = 10.3 min.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
6.0 min, tR (minor) = 5.3 min.
O,O′-Diethyl S-[3-(4-Nitrophenyl)-3-oxo-1-phenylpropyl] Phos-
phorothioate (4h)
Yield: 1.013 g (60%); orange oil.
O,O′-Diethyl S-[1-(4-Chlorophenyl)-3-oxo-3-phenylpropyl] Phos-
1H NMR (500 MHz, CDCl3): δ = 8.27 (d, J = 8.8 Hz, 2 H), 8.07 (d, J = 8.8
Hz, 2 H), 7.40 (d, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 7.24 (t, J =
7.4 Hz, 1 H), 5.00–4.89 (m, 1 H), 4.09–3.94 (m, 4 H), 3.88–3.78 (m, 1
H), 3.70 (dd, J = 17.2, 8.2 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.17 (t, J =
7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 194.8, 150.4, 140.9, 129.2, 128.7,
128.0, 127.6, 123.9, 63.8, 63.7, 46.8, 45.2, 16.0, 15.8.
phorothioate (4e)
Yield: 1.427 g (86%); white crystals; mp 101 °C.
1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 8.1 Hz, 2 H), 7.56 (t, J = 7.3
Hz, 1 H), 7.45 (t, J = 7.6 Hz, 2 H), 7.38 (d, J = 8.2 Hz, 2 H), 7.30–7.24 (m,
2 H), 5.01–4.91 (m, 1 H), 4.13–3.98 (m, 3 H), 3.90–3.79 (m, 2 H), 3.64
(dd, J = 17.2, 8.4 Hz, 1 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.19 (t, J = 7.0 Hz, 3
H).
13C NMR (125 MHz, CDCl3): δ = 195.7, 140.2, 136.4, 133.5, 129.1,
HRMS-EI: m/z calcd for C19H22NO6PSNa [M + Na]+: 446.0803; found:
128.7, 128.1, 63.7, 63.6, 46.1, 44.7, 15.9, 15.8.
446.0790.
25
HRMS-EI: m/z calcd for C19H22ClO4PSNa [M + Na]+: 435.0563; found:
Stereoablative reaction: yield: 85 mg (38%); ee = 78%; [α]D +47.4
435.0564.
(c = 0.01, CHCl3).
Stereoablative reaction: yield: 81 mg (37%); ee = 86%; [α]D25 +92.3 (c
= 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
20.8 min, tR (minor) = 14.9 min.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IC column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
9.7 min, tR (minor) = 13.2 min.
O,O′-Diethyl S-[1-(4-Nitrophenyl)-3-oxo-3-phenylpropyl] Phos-
phorothioate (4i)
Yield: 1.255 g (72%); orange crystals; mp 90–91 °C.
O,O′-Diethyl S-[3-(4-Methoxyphenyl)-3-oxo-1-phenylpropyl]
1H NMR (500 MHz, CDCl3): δ = 8.17 (d, J = 8.7 Hz, 2 H), 7.91 (d, J = 7.3
Hz, 2 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.46 (t, J =
7.7 Hz, 2 H), 5.11–5.02 (m, 1 H), 4.13–3.97 (m, 3 H), 3.95–3.85 (m, 2
H), 3.72 (dd, J = 17.5, 8.6 Hz, 1 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.20 (t, J =
7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 195.3, 149.2, 147.2, 136.1, 133.7,
128.8, 128.0, 123.8, 63.9, 63.7, 45.7, 44.4, 15.9, 15.7.
Phosphorothioate (4f)
Yield: 1.361 g (83%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.90 (d, J = 8.8 Hz, 2 H), 7.42 (d, J = 7.7
Hz, 2 H), 7.29 (t, J = 7.6 Hz, 2 H), 7.21 (t, J = 7.3 Hz, 1 H), 6.90 (d, J =
8.8 Hz, 2 H), 4.99–4.90 (m, 1 H), 4.13–3.95 (m, 3 H), 3.84 (s, 2 H),
3.82–3.69 (m, 2 H), 3.58 (dd, J = 16.8, 8.0 Hz, 1 H), 1.29 (t, J = 7.0 Hz, 3
H), 1.12 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 194.4, 163.7, 141.6, 130.4, 129.6,
HRMS-EI: m/z calcd for C19H22NO6PSNa [M + Na]+: 446.0803; found:
128.5, 127.7, 127.6, 113.8, 63.7, 63.5, 55.5, 45.8, 45.7, 15.9, 15.7.
446.0802.
HRMS-EI: m/z calcd for C20H25O5PSNa [M + Na]+: 431.1058; found:
Stereoablative reaction: yield: 59 mg (30%); ee = 67%; [α]D25 –3.6 (c =
431.1046.
0.01, CHCl3).
25
Stereoablative reaction: yield: 106 mg (49%); ee = 66%; [α]D +52.8
(c = 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IC column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
21.6 min, tR (minor) = 26.3 min.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
8.8 min, tR (minor) = 7.7 min.
O,O′-Diethyl S-[3-Oxo-3-phenyl-1-(m-tolyl)propyl] Phosphoro-
thioate (4j)
Yield: 951 mg (81%); white crystals; mp 53–54 °C.
O,O′-Diethyl S-[1-(4-Methoxyphenyl)-3-oxo-3-phenylpropyl]
1H NMR (500 MHz, CDCl3): δ = 7.93 (d, J = 7.4 Hz, 2 H), 7.55 (t, J = 7.4
Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.24–7.15 (m, 3 H), 7.04 (d, J = 7.0 Hz,
1 H), 4.97–4.88 (m, 1 H), 4.13–3.97 (m, 3 H), 3.86 (dd, J = 17.1, 6.5 Hz,
1 H), 3.82–3.73 (m, 1 H), 3.64 (dd, J = 17.1, 7.9 Hz, 1 H), 2.32 (s, 3 H),
1.30 (t, J = 7.0 Hz, 3 H), 1.15 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 196.0, 141.5, 138.2, 136.6, 133.3,
128.6, 128.5, 128.3, 128.1, 124.1, 63.6, 63.4, 46.4, 45.5, 21.3, 15.9,
15.7.
Phosphorothioate (4g)
Yield: 520 mg (64%); pale yellow crystals; mp 86–87 °C.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 7.4 Hz, 2 H), 7.54 (t, J = 7.4
Hz, 1 H), 7.44 (t, J = 7.7 Hz, 2 H), 7.34 (d, J = 8.6 Hz, 2 H), 6.82 (d, J =
8.6 Hz, 2 H), 4.99–4.91 (m, 1 H), 4.13–3.98 (m, 3 H), 3.89–3.78 (m, 2
H), 3.76 (s, 3 H), 3.64 (dd, J = 17.0, 8.4 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H),
1.18 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 196.1, 159.1, 136.5, 133.5, 133.3,
128.8, 128.6, 128.1, 113.9, 63.7, 63.5, 55.3, 46.5, 45.2, 15.9, 15.7.
HRMS-EI: m/z calcd for C20H25O4PSNa [M + Na]+: 415.1109; found:
415.1109.
HRMS-EI: m/z calcd for C20H25O5PSNa [M + Na]+: 431.1058; found:
413.1059.
Stereoablative reaction: yield: 72 mg (36%); ee = 97%; [α]D25 +31.0 (c
= 0.01, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

H
A. Bacsó et al.
Paper
Synthesis
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 2% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
12.1 min, tR (minor) = 10.9 min.
O,O′-Diethyl S-[1-(1,3-Dihydrosobenzofuranyl)-3-oxo-3-phenyl-
propyl] Phosphorothioate (4n)
Yield: 428 mg (72%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.92 (d, J = 8.2 Hz, 2 H), 7.55 (t, J = 7.4
Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 6.91 (s, 1 H), 6.87 (d, J = 8.0 Hz, 1 H),
6.70 (d, J = 8.0 Hz, 1 H), 5.97–5.84 (m, 2 H), 5.02–4.82 (m, 1 H), 4.14–
4.02 (m, 3 H), 3.95–3.75 (m, 2 H), 3.63 (dd, J = 17.0, 8.5 Hz, 1 H), 1.30
(t, J = 7.1 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 195.9, 147.7, 147.1, 136.4, 135.1,
133.4, 128.67, 128.1, 121.1, 108.1, 108.0, 101.1, 63.9, 63.7, 46.5, 45.6,
15.9, 15.8.
O,O′-Diethyl S-[1-(4-Fluorophenyl)-3-oxo-3-phenylpropyl] Phos-
phorothioate (4k)
Yield: 936 mg (79%); off-white crystals; mp 61–62 °C.
1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 7.7 Hz, 2 H), 7.56 (t, J = 7.3
Hz, 1 H), 7.47–7.37 (m, 4 H), 6.98 (t, J = 8.5 Hz, 2 H), 5.02–4.89 (m, 1
H), 4.09–3.99 (m, 3 H), 3.89–3.78 (m, 2 H), 3.64 (dd, J = 17.1, 8.3 Hz, 1
H), 1.28 (t, J = 7.1 Hz, 3 H), 1.18 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 195.8, 163.0, 161.1, 137.5, 136.4,
HRMS-EI: m/z calcd for C20H23O6PSNa [M + Na]+: 445.0851; found:
133.4, 129.3, 128.7, 128.1, 115.4, 63.7, 63.5, 46.3, 44.8, 15.9, 15.8.
445.0839.
HRMS-EI: m/z calcd for C19H22FO4PSNa [M + Na]+: 419.0858; found:
25
Stereoablative reaction: yield: 61 mg (31%); ee = 87%; [α]D +34.1
419.0849.
(c = 0.01, CHCl3).
Stereoablative reaction: yield: 72 mg (36%); ee = 86%; [α]D25 +43.5 (c
= 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
AD column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
36.5 min, tR (minor) 38.9 min.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
AD column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major)
= 19.2 min, tR (minor) = 24.2 min.
O,O′-Diethyl S-[3-Oxo-1-phenyl-3-(1H-pyrrol-1-yl)propyl] Phos-
phorothioate (4o)
O,O′-Diethyl S-[1,3-Bis(4-chlorophenyl)-3-oxopropyl] Phosphoro-
Yield: 111 mg (15%); dark brown oil.
thioate (4l)
1H NMR (500 MHz, CDCl3): δ = 7.42 (d, J = 7.2 Hz, 2 H), 7.35–7.28 (m, 4
H), 7.28–7.23 (m, 1 H), 6.27 (t, J = 2.3 Hz, 2 H), 4.98–4.85 (m, 1 H),
4.07–3.99 (m, 2 H), 3.87–3.72 (m, 2 H), 3.51 (dd, J = 16.4, 8.3 Hz, 1 H),
1.29 (t, J = 6.8 Hz, 3 H), 1.17 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 166.8, 140.6, 128.7, 128.1, 127.6,
119.0, 113.5, 63.9, 63.7, 45.6, 42.6, 15.9, 15.8.
Yield: 721 mg (40%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J = 8.5 Hz, 1 H), 7.42 (d, J = 8.5
Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.31–7.23 (m, 1 H), 4.98–4.87 (m, 1
H), 4.11–3.98 (m, 2 H), 3.85 (dd, J = 17.1, 6.3 Hz, 1 H), 3.60 (dd, J =
17.2, 8.4 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 1 H), 1.19 (t, J = 7.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 194.6, 140.0, 134.7, 133.6, 129.5,
HRMS-EI: m/z calcd for C17H22NO4PSNa [M + Na]+: 390.0905; found:
129.0, 128.7, 63.8, 63.6, 46.1, 44.7, 16.0, 15.8.
390.0901.
HRMS-EI: m/z calcd for C19H21Cl2O4PSNa [M + Na]+: 469.0173; found:
Stereoablative reaction: yield: 54 mg (28%); ee = 93%; [α]D25 +23.7 (c
469.0157.
= 0.01, CHCl3).
25
Stereoablative reaction: yield: 64 mg (28%); ee = 86%; [α]D +76.0
(c = 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 220 nm, tR (major) =
4.9 min, tR (minor) = 5.9 min.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IC column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
7.7 min, tR (minor) = 12.3 min.
O,O′-Diethyl S-(3-Oxo-1-phenylbutyl) Phosphorothioate (4p)
Yield: 980 mg (52%); yellow oil.
O,O′-Diethyl S-[1,3-Bis(4-methoxyphenyl)-3-oxopropyl] Phospho-
rothioate (4m)
1H NMR (500 MHz, CDCl3): δ = 7.35 (d, J = 7.7 Hz, 2 H), 7.28 (t, J = 7.6
Hz, 2 H), 7.21 (t, J = 7.3 Hz, 1 H), 4.77–4.68 (m, 1 H), 4.05–3.93 (m, 3
H), 3.79–3.68 (m, 1 H), 3.24 (dd, J = 17.1, 7.0 Hz, 1 H), 3.08 (dd, J =
17.1, 7.8 Hz, 1 H), 2.08 (s, 3 H), 1.25 (t, J = 7.0 Hz, 3 H), 1.11 (t, J = 7.1
Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 204.3, 141.5, 128.6, 127.7, 127.5, 63.6,
63.4, 50.9, 45.0, 30.3, 15.9, 15.7.
Yield: 604 mg (39%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 8.8 Hz, 2 H), 7.33 (d, J = 8.6
Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 6.81 (d, J = 8.6 Hz, 2 H), 4.97–4.86 (m,
1 H), 4.13–3.97 (m, 3 H), 3.84 (s, 3 H), 3.83–3.77 (m, 2 H), 3.76 (s, 3 H),
3.57 (dd, J = 16.6, 8.4 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.17 (t, J = 7.1
Hz, 3 H).
HRMS-EI: m/z calcd for C14H21O4PSNa [M + Na]+: 339.0796; found:
339.0792.
13C NMR (125 MHz, CDCl3): δ = 194.6, 163.7, 159.0, 133.6, 133.4,
129.7, 128.8, 113.9, 113.8, 63.6, 63.4, 55.4, 55.2, 46.1, 45.5, 15.9, 15.8.
HRMS-EI: m/z calcd for C21H27O6PSNa [M + Na]+: 461.1164; found:
Stereoablative reaction: yield: 79 mg (40%); ee = 10%; [α]D25 –4.3 (c =
0.01, CHCl3).
461.1146.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 211 nm, tR (major) =
6.0 min, tR (major) = 6.5 min.
Stereoablative reaction: yield: 99 mg (42%); ee = 75%; [α]D25 +71.4 (c
= 0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 2% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
39.8 min, tR (minor) = 35.9 min.
O,O′-Diethyl S-(4-Oxo-4-phenylbutan-2-yl) Phosphorothioate (4q)
Yield: 1.257 g (94%); yellow oil.
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1H NMR (500 MHz, CDCl3): δ = 7.95 (d, J = 7.3 Hz, 2 H), 7.55 (t, J = 7.4
Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 4.22–4.03 (m, 4 H), 3.95–3.83 (m, 1
H), 3.60 (dd, J = 16.9, 5.3 Hz, 1 H), 3.19 (dd, J = 16.9, 8.1 Hz, 1 H), 1.50
(d, J = 6.9 Hz, 3 H), 1.32 (dt, J = 9.2, 7.1 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 197.1, 136.6, 133.3, 128.7, 128.1, 63.8,
63.5, 46.8, 37.8, 23.1, 16.0, 15.9.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 7.3 Hz, 2 H), 7.56 (t, J = 7.4
Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H), 7.28–7.13 (m, 5 H), 4.21–4.05 (m, 4
H), 3.91–3.77 (m, 1 H), 3.70 (dd, J = 17.1, 5.5 Hz, 1 H), 3.33 (dd, J =
17.1, 7.7 Hz, 1 H), 2.96–2.87 (m, 1 H), 2.81–2.72 (m, 1 H), 2.22–2.04
(m, 2 H), 1.31 (dt, J = 12.8, 7.1 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 197.3, 140.9, 136.7, 133.3, 128.6,
128.4, 128.4, 128.1, 126.1, 63.8, 63.7, 45.3, 42.7, 37.3, 33.2, 16.1, 16.0.
HRMS-EI: m/z calcd for C21H27O4PSNa [M + Na]+: 429.1265; found:
HRMS-EI: m/z calcd for C14H21O4PSNa [M + Na]+: 339.0796; found:
339.0793.
429.1256.
Stereoablative reaction: yield: 85 mg (42%); ee = 30%; [α]D25 +6.1 (c =
0.01, CHCl3).
Stereoablative reaction: yield: 107 mg (50%); ee = 14%; [α]D25 –1.6 (c =
0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
AD column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
8.8 min, tR (minor) = 9.8 min.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
AD column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
11.2 min, tR (minor) = 12.4 min.
O,O′-Diethyl S-(3-Cyclopentyl-3-oxo-1-phenylpropyl) phosphoro-
thioate (4r)
O,O′-Diphenyl S-(3-Oxo-1,3-diphenylpropyl) Phosphorothioate
[(+)-5a]
Yield: 771 mg (59%); pale yellow oil.
Stereoablative reaction: yield: 99 mg (38%); ee = 49%; [α]D25 +2.7 (c =
0.01, CHCl3). Enantioselectivity was determined by HPLC analysis
with a Chiralpak IB column, 10% EtOH in hexanes, 1.0 mL/min, λ =
242 nm, tR (major) = 8.5 min, tR (minor) = 6.5 min.
1H NMR (500 MHz, CDCl3): δ = 7.37 (d, J = 7.6 Hz, 2 H), 7.29 (t, J = 7.5
Hz, 2 H), 7.22 (t, J = 7.3 Hz, 1 H), 4.81–4.72 (m, 1 H), 4.10–4.01 (m, 2
H), 4.01–3.93 (m, 1 H), 3.74–3.64 (m, 1 H), 3.26 (dd, J = 17.1, 6.9 Hz, 1
H), 3.10 (dd, J = 17.1, 7.8 Hz, 1 H), 2.82–2.72 (m, 1 H), 1.77–1.66 (m, 3
H), 1.62–1.47 (m, 5 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.10 (t, J = 7.1 Hz, 3 H).
O,O′-Diphenyl S-(3-Oxo-1-phenylbutyl) Phosphorothioate (5b)
13C NMR (125 MHz, CDCl3): δ = 208.5, 141.8, 128.5, 127.6, 127.5, 63.6,
63.4, 51.7, 49.2, 45.1, 28.4, 25.8, 15.9, 15.7.
Yield: 568 mg (35%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.41–7.03 (m, 17 H), 4.99–4.91 (m, 1
H), 3.22 (dd, J = 17.1, 5.9 Hz, 1 H), 3.14 (dd, J = 17.1, 8.8 Hz, 1 H), 1.99
(s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 204.1, 150.2, 140.3, 129.7, 128.7,
128.0, 127.6, 125.6, 120.7, 50.8, 46.3, 30.1.
HRMS: m/z calcd for C18H27O4PSNa [M + Na]+: 393.1265; found:
393.1255.
Stereoablative reaction: yield: 95 mg (49%); ee = 21%; [α]D25 +3.7 (c =
0.01, CHCl3).
Enantioselectivity was determined by HPLC analysis with a Chiralpak
AD column, 15% EtOH in hexanes, 0.5 mL/min, λ = 242 nm, tR (major) =
17.1 min, tR (minor) =17.7 min.
HRMS-EI: m/z calcd for C22H21O4PSNa [M + Na]+: 435.0796; found:
435.0776.
Stereoablative reaction: yield: 162 mg (76%); ee = 3%.
O,O′-Diethyl S-(1-Cyclohexyl-3-oxo-3-phenylpropyl) Phosphoro-
thioate (4s)
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IB column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
5.0 min, tR (minor) = 6.0 min.
Yield: 1.300 g (75%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 7.3 Hz, 2 H), 7.55 (t, J = 7.4
Hz, 1 H), 7.46 (t, J = 7.6 Hz, 2 H), 4.20–4.04 (m, 4 H), 3.84–3.75 (m, 1
H), 3.55 (dd, J = 17.1, 5.8 Hz, 1 H), 3.36 (dd, J = 17.1, 7.5 Hz, 1 H), 1.89
(d, J = 12.4 Hz, 1 H), 1.81–1.71 (m, 4 H), 1.65 (d, J = 12.8 Hz, 1 H), 1.39–
0.98 (m, 11 H).
13C NMR (125 MHz, CDCl3): δ = 197.4, 136.7, 133.2, 128.6, 128.2, 63.8,
63.7, 48.7, 42.8, 41.9, 30.5, 29.2, 26.2, 16.0, 15.9.
O,O′-Diphenyl S-(4-Oxo-4-phenylbutan-2-yl) Phosphorothioate
(5c)
Yield: 1.561 g (94%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J = 7.5 Hz, 2 H), 7.55 (t, J = 7.4
Hz, 1 H), 7.43 (d, J = 7.7 Hz, 2 H), 7.37–7.11 (m, 12 H), 4.11–3.98 (m, 1
H), 3.49 (dd, J = 17.1, 4.5 Hz, 1 H), 3.16 (dd, J = 17.1, 8.4 Hz, 1 H), 1.46
(d, J = 6.8 Hz, 3 H).
HRMS-EI: m/z calcd for C19H29O4PSNa [M + Na]+: 407.1422; found:
407.1409.
13C NMR (125 MHz, CDCl3): δ = 196.8, 150.1, 136.4, 133.4, 128.6,
Stereoablative reaction: yield: 108 mg (53%); ee = 29%; [α]D25 –2.7 (c =
128.1, 125.7, 120.9, 46.6, 39.2, 22.8.
HRMS-EI: m/z calcd for C22H21O4PSNa [M + Na]+: 435.0796; found:
0.01, CHCl3).
435.0786.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
AD column, 10% EtOH in hexanes, 1.0 mL/min, λ = 242 nm, tR (major) =
6.4 min, tR (minor) = 9.5 min.
Stereoablative reaction: yield: 170 mg (80%); ee = <1%.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
AD column, 10% EtOH in hexanes, 1.5 mL/min, λ = 242 nm, tR (major) =
22.2 min, tR (minor) = 17.7 min.
O,O′-Diethyl S-(1-Oxo-1,5-diphenylpentan-3-yl) Phosphorothioate
(4t)
Yield: 1.262 g (77%); yellow oil.
O,O′-Diphenyl S-(3-Cyclopentyl-3-oxo-1-phenylpropyl) Phospho-
rothioate (5d)
Yield: 264 mg (57%); yellow oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K

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A. Bacsó et al.
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1H NMR (500 MHz, CDCl3): δ = 7.34–7.07 (m, 15 H), 5.05–4.94 (m, 1
H), 3.25 (dd, J = 17.1, 5.8 Hz, 1 H), 3.16 (dd, J = 17.1, 8.9 Hz, 1 H), 2.76–
2.58 (m, 1 H), 1.72–1.58 (m, 4 H), 1.58–1.39 (m, 4 H).
trans-ent-2-(4-Chlorophenyl)-4-phenylthietane (trans-ent-6)
Prepared by using the retro-Michael product of racemic 4e with
thiourea catalyst 1c and prolinol 1h; yield: 52 mg (20%); white crys-
tals; mp 111–115 °C.
13C NMR (125 MHz, CDCl3): δ = 208.3, 150.1, 140.7, 129.7, 128.6,
1H NMR (500 MHz, CDCl3): δ = 7.53–7.21 (m, 9 H), 4.92–4.79 (m, 2 H),
3.46–3.36 (m, 1 H), 3.19–3.09 (m, 1 H).
127.8, 127.6, 125.5, 120.7, 51.5, 49.1, 46.4, 28.3, 25.8.
HRMS-EI: m/z calcd for C26H27O4PSNa [M + Na]+: 489.1265; found:
489.1262.
The NMR data are consistent with the reported data.
[α]D25 –3.1 (c = 0.001, CHCl3); dr = 10:1; ee = 98.6%.
Stereoablative reaction: yield: 109 mg (44%); ee = 7%.
Enantioselectivity was determined by HPLC analysis with a Chiralpak
IC column, 15% EtOH in hexanes, 0.5 mL/min, λ = 210 nm, tR (major) =
10.2 min, tR (minor) = 14.5 min.
Diastereoselectivity and enantioselectivity was determined by HPLC
analysis with a Chiralpak OJ column, 2% EtOH in hexanes, 1.0 mL/min,
λ = 227 nm, tR (major) = 11.5 min, tR (minors) = 10.7, 13.5, and 14.4
min.
Stereoselective CBS Reduction;14c General Procedure
The precatalyst 1h or ent-1h (52.5 mg, 0.1 mmol) was dissolved in an-
hyd THF (1 mL) and trimethyl borate (13 mg, 14 μL, 0.12 mmol) was
added. The mixture was stirred at r.t. for 1 h. Then BH3·SMe2 (0.105
mL, 1 mmol, 1 equiv BH3) was introduced under N2 atmosphere at r.t.,
followed by slow addition of the enantioenriched phosphorothioate
adduct 4e (1.0 mmol) in anhyd THF (1.5 mL) over a period of 1 h. The
reaction mixture was stirred for an additional 1 h for completion.
Then it was cooled to 0 °C and slowly quenched with MeOH (1.5 mL)
(vigorous hydrogen gas evolution was observed). Then NaH (72 mg,
3.0 mmol, mineral oil-free) was added, and the reaction mixture was
stirred overnight at r.t. H2O (10 mL) was added and the white emul-
sion was extracted with Et2O (3 × 15 mL) and dried (Na2SO4). The
crude product was purified by column chromatography (Biotage® KP-
Sil 10 g, pure hexanes for the product, and hexanes/EtOAc, 3:1 for the
contaminants). The product was obtained as a white crystalline solid.
cis-ent-2-(4-Chlorophenyl)-4-phenylthietane (cis-ent-6)
Using the retro-Michael product of racemic 4e with thiourea catalyst
1c and prolinol ent-1h; yield: 65 mg (25%); white crystals; mp 118–
122 °C.
1H NMR (500 MHz, CDCl3): δ = 7.53–7.21 (m, 9 H), 4.92–4.79 (m, 2 H),
3.46–3.36 (m, 1 H), 3.19–3.09 (m, 1 H).
The NMR data are consistent with the reported data.
[α]D25 –29.1 (c = 0.001, CHCl3); dr = 8:1; ee = 99.8%.
Diastereoselectivity and enantioselectivity was determined by HPLC
analysis with a Chiralpak OJ column, 2% EtOH in hexanes, 1.0 mL/min,
λ = 227 nm, tR (major) = 14.5 min, tR (minors) = 10.7, 11.6, and 13.6
min.
Acknowledgment
cis-2-(4-Chlorophenyl)-4-phenylthietane (cis-6)
Prepared by using the retro-Michael product of racemic 4e with
Takemoto catalyst 1d and prolinol 1h; yield: 94 mg (36%); white crys-
tals; mp 118–122 °C
1H NMR (500 MHz, CDCl3): δ = 7.53–7.21 (m, 9 H), 4.92–4.79 (m, 2 H),
We are grateful for the financial support from OTKA (PD 112268 and
K116150). The authors thank Ágnes Gömöry for HRMS measure-
ments. Sz. V. thanks for support of János Bolyai Scholarship of Hun-
garian Academy of Sciences.
3.46–3.36 (m, 1 H), 3.19–3.09 (m, 1 H).
The NMR data are consistent with the reported data.
[α]D25 +28.7 (c = 0.001, CHCl3); dr = 22:1; ee = 99.3%.
Supporting Information
Supporting information for this article is available online at
Diastereoselectivity and enantioselectivity was determined by HPLC
analysis with a Chiralpak OJ column, 2% EtOH in hexanes, 1.0 mL/min,
λ = 227 nm, tR (major) = 13.2 min, tR (minors) = 10.5, 11.3, and 14.1
min.
http://dx.doi.org/10.1055/s-0036-1588612.
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References
trans-2-(4-Chlorophenyl)-4-phenylthietane (trans-6)
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1H NMR (500 MHz, CDCl3): δ = 7.53–7.21 (m, 9 H), 4.92–4.79 (m, 2 H),
3.46–3.36 (m, 1 H), 3.19–3.09 (m, 1 H).
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[α]D25 +3.7 (c = 0.001, CHCl3); dr = 17:1; ee = 99.6%.
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(13) S = ln[(1 – c)(1 – ee)]/ln[(1 – c)(1 + ee)], where c = conv./100 and
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K