Amino thiols versus amino alcohols in the asymmetric alkynylzinc addition to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2009.05.029

A series of modular amino thiol and amino alcohol ligands have been synthesized in enantiopure form from common enantiopure precursors. Their structures have been optimized for performance in the asymmetric alkynylzinc addition to aldehydes, and a direct

Full text of DOI:10.1016/j.tetasy.2009.05.029

Tetrahedron: Asymmetry 20 (2009) 1413–1418
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Amino thiols versus amino alcohols in the asymmetric alkynylzinc addition
to aldehydes
Sílvia Subirats a, Ciril Jimeno a, Miquel A. Pericàs a,b,
*
a Institute of Chemical Research of Catalonia (ICIQ), Avda. Països Catalans, 16, 43007 Tarragona, Spain
b Departament de Química Orgànica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of modular amino thiol and amino alcohol ligands have been synthesized in enantiopure form
from common enantiopure precursors. Their structures have been optimized for performance in the
asymmetric alkynylzinc addition to aldehydes, and a direct comparison of the effect of the S and O coor-
dinating atoms on the catalytic outcome of these ligands has been performed. Amino thiols have shown
to be superior as ligands for this type of chemistry.
Received 20 April 2009
Accepted 8 May 2009
Available online 18 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The use of chiral amino thiol ligands in asymmetric organozinc
additions to aldehydes has been developed in view of the excellent
results obtained with these ligands in conversion and stereoselec-
tivity. This was attributed to a beneficial effect of the coordinating
sulfur atom in enhancing the reactivity of the dialkylzinc com-
pounds, since sulfur has a greater affinity for Zn than oxygen.
Moreover, aminothiolate–zinc complexes are considered better Le-
wis acids than aminoalcoholate–zinc complexes, which enhance
the reactivity of the aldehyde.1
We based our approach on the preparation of modular ligands
(amino alcohols and amino thiols) arising from a common amino
alcohol intermediate. In turn, these compounds can be readily pre-
pared from enantiopure (S,S)-phenylglycidol using a well-estab-
lished O-alkylation-ring opening sequence developed by our
group (Scheme 1).6,7
NR'2
O
Although some amino thiol ligands exhibit a clearly superior
performance than amino alcohols in carbonyl additions, to the best
of our knowledge only one direct comparison of structurally iden-
tical ligands has been carried out in the asymmetric diethylzinc
addition to aldehydes. Kang et al. showed that amino thiols en-
hanced reaction rate, enantioselectivity, and asymmetric amplifi-
cation, and discussed their results in terms of changes in the
reaction mechanism. In particular, it was suggested that besides
increasing the amount of free monomeric catalyst, aminothio-
late–zinc dimers could behave as efficient catalysts as well.2
The asymmetric alkynylation of aldehydes using amino thiols
has scarcely been studied.3 In fact, only one example has been de-
scribed in the literature, with limited success.4 A related asymmet-
ric vinylation using amino thiols as chiral ligands has also been
reported.5 Herein we report on the successful use of amino thiol li-
gands in the asymmetric alkynylation of aldehydes (up to quanti-
tative yield, up to 90% ee). Comparison with the otherwise
identical amino alcohols allowed us to establish that S-containing
ligands are superior for this particular application.
Ph
OH
OR
Ph
OR
OH
XH
R'2
N
Ph
Ph
OR
NR'2
1 X=S
2
X=O
Scheme 1. Strategy for the preparation of amino thiols and amino alcohols.
Besides the electronic characteristics arising from the thiol/hy-
droxyl groups, the steric effects of the ligands must also be modu-
lated in order to fine-tune catalytic activity and enantioselectivity.8
The dialkylamino and O-alkyl groups were selected for this pur-
pose. With respect to the amino substituent, a piperidino group
was chosen due to its proven effectivity in related ligands for
asymmetric diethylzinc additions.6,7 A dimethylamino group was
also used to minimize steric interactions. With respect to the alk-
oxy group, two extreme O-alkyl groups (methyl and trityl) were
* Corresponding author.
E-mail address: mapericas@iciq.es (M.A. Pericàs).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.029

1414
S. Subirats et al. / Tetrahedron: Asymmetry 20 (2009) 1413–1418
Table 1
Screening of ligands 1–2
also introduced into the structure to control the steric hindrance of
that part of the ligand.8
OH
1) ZnMe2 2M in toluene,
Once the amino alcohol intermediates had been prepared in
enantiopure form from phenylglycidol, they were treated with
methanesulfonyl chloride and triethylamine in dichloromethane
to form an aziridinium cation, which was not isolated but treated
in situ with S or O nucleophiles, in this case, potassium thioacetate
or sodium p-nitrobenzoate. The ring opening of this aziridinium
intermediate took place stereospecifically with complete regiose-
lectivity. It should be pointed out that the products are in fact
regioisomers of the starting amino alcohols. The reduction or
hydrolysis of these compounds yielded the corresponding amino
thiols and amino alcohols, in good to excellent overall yields
(Scheme 2). We had prepared ligand 1aa before by means of this
sequence, and it proved to be an extremely active and enantiose-
lective amino thiol for diethylzinc additions to aldehydes.9
Et2O, 50 ºC, 1 h
Ph
2) 10 mol% 1 or 2, 0 ºC
Ph
eeb (%)
3) PhCHO, 0 ºC, 18 h
Entry
Ligand
Conv.a (%)
1
2
3
4
5
6
7
1aa
1ab
1ba
1bb
2aa
2ab
2bb
93
90
92
36
71
66
61
87
71
73
67
31
29
10
Determined by 1H NMR on the crude product.
Determined by HPLC in a Chiralcel OD column.
a
b
SH
1) MsCl, Et3N
Ph
OR
2) 10% aq. AcSK
3) DIBALH
Changes in the concentration did not improve the results. Per-
NR'2
NR'2
forming the reaction under more concentrated conditions fur-
nished the propargyl alcohol in quantitative yield, but at the
expense of enantioselectivity (entry 2). On the other hand, dilution
only made the reaction slower, and the product was isolated with
identical ee (entry 3). Reactions performed in toluene or dichloro-
methane increased the conversion too, but again with diminished
ee’s, especially in the case of CH2Cl2 (entries 4 and 5). The enanti-
oselectivity did not noticeably change at different temperatures,
but reactions were much slower below 0 °C (entries 1 and 6 vs en-
tries 7 and 8). In conclusion, diethyl ether turns out to be the sol-
vent of choice, whereas a temperature between 0 and 25 °C is
required in order to achieve reasonable reaction rates.
1
Ph
OR
OH
OH
1) MsCl, Et3N
Ph
OR
2) p-NBA, NaOH
3) MeONa, MeOH
NR'2
2
Ligand
1aa
1ab
1ba
1bb
2aa
R
NR’2
piperidino
NMe2
piperidino
NMe2
piperidino
NMe2
NMe2
Overall yield/%
CPh3
CPh3
CH3
89
62
Quant.
49
61
54
CH3
Finally the scope of this catalytic system was checked under the
conditions selected above (Table 3).
CPh3
CPh3
CH3
2ab
2bb
57
The optimal catalyst 1aa furnishes the propargyl alcohols in high
yields and ee’s for benzaldehyde and naphthaldehyde, and arylacet-
ylenes with electron-withdrawing groups (entries 1–6 and 12).
Other aromatic aldehydes also react gently under these conditions
albeit with somewhat lower enantioselectivity (entries 7, 13, 14,
and 15). On the other hand, p-anisaldehyde reaches 90% ee although
with a poorer yield of only 29% (entry 11). A particular case is 2,6-
dimethoxybenzaldehyde (entry 16) where the low yield and ee can
be attributed to the steric hindrance around the carbonyl group.
These results suggest important electronic effects on both the con-
version and stereoselectivity of the reaction. The addition of alkynes
Scheme 2. Synthesis of amino thiols 1 and amino alcohols 2.
With the whole set of ligands in hand, we proceeded to test
them in the asymmetric alkynylzinc addition to aldehydes. The
alkynylzinc compounds were generated by mixing the acetylene
with ZnMe2,10 following Soai’s original procedure.11 This method
has found widespread application because there is no necessity
to use other metal sources to generate the active catalyst. Typi-
cally, amino alcohols, imino alcohols, or salen-type ligands have
been employed as chirality sources.12 Herein, we chose phenyl-
acetylene, dimethylzinc, and benzaldehyde as reagents, and
diethyl ether as solvent. After the generation of methyl(phenyleth-
ynyl)zinc at 50 °C, the asymmetric addition was carried out at 0 °C,
using a 10 mol % of ligand. The results are summarized in Table 1.
It can bee seen that amino thiols were superior ligands for this
reaction, leading in all cases except for 1bb to higher yields. Enanti-
oselectivities were also much higher when thiol ligands were em-
ployed (compare entries 1–5, 2–6, and 4–7, Table 1). Thus, it can
be seen that structurally identical ligands show higher activities
and enhanced stereoselectivities when a thiol moiety is present in-
stead of a hydroxyl group. Regarding the optimal structure of the li-
gand, it is also clear from Table 1 that both a piperidino ring and a
bulky trityl group are key to achieving high ee’s in the reaction.
Yields seem to be less dependent on the ligand structure, but more
dependent on the electronic nature of the ligand. Thus, amino thiols
generate the propargyl alcohol with ca. 90% conversion whereas this
type of amino alcohol furnishes the product in 60–70% conversion.
Next, the reaction conditions were studied using the optimal li-
gand 1aa in the same reaction (Table 2). The effects of solvent, con-
centration, and temperature on the reaction outcome were
analyzed.
Table 2
Optimization of the alkynyl addition with ligand 1aa
OH
1) ZnMe2 2M in toluene,
Et2O, 50 ºC, 1 h
Ph
2) 10 mol% 1aa
3) PhCHO, T, 18 h
Ph
Entry
Solvent
T (°C)
Conv.a (%)
eeb (%)
1
Et2O
Et2O
Et2O
Toluene
CH2Cl2
Et2O
Et2O
Et2O
0
0
0
0
0
25
ꢀ10
ꢀ20
93
100
82
100
98
91
78
54
87
79
87
81
51
89
86
86
2c
3d
4
5
6
7
8
a
Determined by 1H NMR on the crude product.
Determined by HPLC in a Chiralcel OD column.
Concentration was 10 times higher than in entry 1.
Diluted twice with respect to entry 1.
b
c
d

S. Subirats et al. / Tetrahedron: Asymmetry 20 (2009) 1413–1418
Table 3 (continued)
1415
Table 3
Substrate scope in the alkynyl addition with ligand 1aa
Entry
Producta
Conv.b (%)
eec (%)
1) ZnMe2 2M in toluene,
Et2O, 50 ºC, 1 h
OH
OH
Y
X
12
72
71
67
2) 10 mol% 1aa
3) YCHO, T, 18 h
X
Ph
H3C
O
OH
OH
Entry
1
Producta
Conv.b (%)
eec (%)
13
70
OH
OH
OH
Ph
93
87
OMe
Ph
14
15
30
93
9
43
46
Ph
OMe
OH
2
3
95
83
84
F
Ph
100
Cl
OH
16
100
5
OH
OH
Ph
Cl
4
98
86
a
Absolute configuration determined by comparison of the specific rotation or
chiral HPLC traces with the literature.
Conversion determined by 1H NMR of the crude product. In some cases, pure
b
product was isolated by flash chromatography and yield matched with conversion.
c
Ee determined by chiral HPLC analysis.
5
6
85
64
66
54
other than arylacetylenes resulted in moderate ee’s (entries 8–10).
Finally, the use of aliphatic aldehydes such as cyclohexanecarbalde-
hyde and hexanal (entries 17 and 18) furnished the corresponding
propargyl alcohols in high yield but moderate enantioselectivity.
The reaction was found to yield the (R)-enantiomer for some propar-
gyl alcohols, by comparison of their specific rotation or chiral HPLC
retention times with previously reported data.12,13 The same config-
uration is assumed for the remainder of the products.
OMe
OH
5
OH
OH
A simple model can be built to explain these results (Fig. 1). The
aminothiolate–methylzinc complex can coordinate both the alky-
nylzinc and the aldehyde, in a similar fashion as the well-known
amino alcohols for the asymmetric addition of diethylzinc to alde-
hydes. The aldehyde must then adopt the positioning depicted in
Figure 1 (with the phenyl group anti to the aminothiolate–zinc
complex) to minimize steric repulsion. In this manner, alkynyl
transfer can take place to afford carbonyls with the observed sense
of enantiocontrol.
7
8
93
52
27
26
OEt
TMS
OH
Ph3CO
CH3
9
10
11
29
64
75
90
85
77
H
Ph
HO
Zn
(R)
Ph
H
N
MeO
S
O
R
OH
Zn
H3C
R
Ph
Figure 1. Stereoselectivity model.
OH
3. Conclusions
Ph
In conclusion, we have shown how amino thiols behave as im-
proved ligands with respect to structurally identical amino alco-
hols in the asymmetric alkynylation of aldehydes using
F

1416
S. Subirats et al. / Tetrahedron: Asymmetry 20 (2009) 1413–1418
organozinc reagents. Much better yields and stereoselectivities can
be reached by simply changing the hydroxyl group by a thiol,
although the ee is very dependent on the ligand structure too. Ami-
no thiols are particularly promising for the addition of arylacetyl-
enes to aromatic aldehydes with good yields and ee’s.
was purified by flash chromatography (SiO2–2.5% Et3N, and a gra-
dient of hexane/AcOEt 0:100). Yield = 89%. 1H NMR (400 MHz,
CDCl3)
d
1.25 (s, 6H), 2.32 (m, 4H), 3.07 (dd, J1 = 5.6 Hz,
J2 = 12.3 Hz, 1H), 3.31 (dd, J1 = 5.4 Hz, J2 = 9.8 Hz, 1H), 3.39 (dd,
J1 = 5.8 Hz, J2 = 9.8 Hz, 1H), 4.22 (d, J = 6.8 Hz, 1H), 7.20–7.32 (m,
15H), 7.46–7.50 (m, 5H) ppm; DEPTQ NMR (100 MHz, CDCl3): d
24.6 (CH2), 26.7 (CH2), 44.3 (CH), 51.8 (CH2), 61.1 (CH2), 70.6
(CH), 126.6 (CH), 127.0 (CH), 127.7 (CH), 127.8 (CH), 128.1 (CH),
128.8 (CH), 129.3 (CH), 142.60 (C), 144.0 (C) ppm; IR 3057, 3024,
4. Experimental
4.1. General procedures
2931, 2848, 2799, 1596, 1489, 1444, 1061, 767, 743, 703 cmꢀ1
;
½
a 2D0
ꢂ
¼ þ52:7 (c 2.1, CDCl3); HRMS (ESI+ve) calcd for C33H35NSOꢃH+
Reactions were performed in flame-dried flasks sealed under an
argon atmosphere. Liquids were transferred into septum-capped
flasks via syringe or cannula. Anhydrous solvents were obtained
from a solvent purification system and were used as collected.
Chemicals were purchased from Aldrich or Acros. Aldehydes were
distilled prior to use, and all other reagents were used as received.
MS spectra were recorded with a Waters LCT Premier HPLC-TOF
spectrometer that may be operated in ESI or APCI modes, or with
a Waters GCT GC-TOF spectrometer with CI or EI options. Optical
rotations were measured with a JASCO P-1030 polarimeter at
589 nm using 100 ꢁ 3.5 mm or 10 ꢁ 10 mm cells. NMR spectra
were recorded with a Bruker Avance 400 Ultrashield spectrometer,
which records 1H NMR spectra at 400 MHz with TMS as the inter-
nal standard, and 13C NMR spectra at 100 MHz with CDCl3 as the
reference. Coupling constants J are in hertz and chemical shifts d
in parts per million. IR spectra were measured with a Bruker Ten-
sor 27 FTIR with an ATR cell. HPLC analyses were performed in an
Agilent 110 Series apparatus equipped with UV–vis detector and
autosampler. Chiral analyses were carried out using a Chiralcel
OD-H column, with hexane/isopropanol mixtures as eluent.
494.2518, found 494.2531.
4.1.3. Synthesis of (S)-(1S,2R)-2-(dimethylamino)-1-phenyl-3-
(trityloxy)propyl ethanethioate Ac-1ab
The procedure was analogous to that used for Ac-1aa.
Yield = 88%. 1H NMR (400 MHz, CDCl3): d 2.15 (s, 3H), 2.17 (s,
6H), 3.14–3.20 (m, 1H), 3.30–3.31 (m, 2H), 4.82 (d, J = 7.7 Hz,
1H), 7.17–7.29 (m, 16H), 7.43–7.47 (m, 4H) ppm; DEPTQ NMR
(100 MHz, CDCl3): d 30.5 (CH3), 42.4 (CH3), 48.8 (CH), 60.8 (CH2),
67.7 (CH), 127.0 (CH), 127.0 (CH), 127.8 (CH), 128.2 (CH), 128.4
(CH), 128.6 (CH), 128.9 (CH), 140.9 (C), 143.9 (C), 194.3 (C) ppm;
IR 3057, 3026, 2929, 2870, 2778, 2360, 1686, 1597, 1490, 1447,
1068, 762, 745, 696 cmꢀ1; ½a D20
¼ þ101:3 (c 0.046, CDCl3); HRMS
ꢂ
(ESI+ve) calcd for C32H33NO2SꢃNa+ 518.2130, found 518.2106.
4.1.4. Synthesis of (1S,2R)-2-(dimethylamino)-1-phenyl-3-
(trityloxy)propane-1-thiol 1ab
The procedure was analogous to the one described for 1aa.
Yield = 70%. 1H NMR (400 MHz, CDCl3): d 2.09 (s, 6H), 2.98–3.03
(m, 1H), 3.29 (dd, J1 = 5.6 Hz, J1 = 10.0 Hz, 1H), 3.39 (dd,
J1 = 4.2 Hz, J1 = 10.0 Hz, 1H), 4.18 (d, J = 7.4 Hz, 1H), 7.13–7.22 (m,
16H), 7.35–7.38 (m, 4H) ppm; DEPTQ NMR (100 MHz, CDCl3): d
42.7(CH3), 44.5 (CH), 60.7 (CH2), 69.6 (CH), 126.9 (CH), 126.9
(CH), 127.1 (CH), 127.8 (CH), 127.9 (CH), 128.0 (CH), 128.2 (CH),
128.9 (CH), 129.4 (CH), 142.7 (C), 143.9 (C), 147.2 (C) ppm; IR
3056, 3024, 2928, 2869, 2826, 2777, 1736, 1596, 1490, 1447,
4.1.1. Synthesis of (S)-(1S,2R)-1-phenyl-2-(piperidin-1-yl)-3-
(trityloxy)propyl ethanethioate Ac-1aa
(1R,2R)-1-Phenyl-1-(piperidin-1-yl)-3-(trityloxy)propan-2-ol (1.3 g,
2.72 mmol) was weighed in a flame-dried round-bottomed flask
under argon, and dissolved in anhydrous dichloromethane
(20 mL. The solution was cooled to 0 °C. Then triethylamine
(1.26 mL 8.99 mmol) and methanesulfonyl chloride (0.34 mL
4.36 mmol) were added. After 2 h at 0 °C, a 10% aqueous thioace-
tate solution was added (1.21 g AcSK, 10.59 mmol). The mixture
was left reacting overnight, while reaching room temperature
slowly. Then it was quenched with water and extracted with
dichloromethane (ꢁ3). The organic layers were washed with a 1%
aqueous hydrochloric acid solution (50 mL and a bicarbonate solu-
tion (50 mL, dried with anhydrous sodium sulfate, and evaporated
under vacuum. The product was isolated in pure form and used
without further purification. Quantitative yield. 1H NMR
(400 MHz, CDCl3): d 1.23 (s, 6H), 2.18 (s, 3H), 2.25–2.34 (m, 2H),
2.38–2.47 (m, 2H), 3.09–3.17 (m, 1H), 3.18–3.24 (m, 1H), 3.35
(dd, J1 = 6.6 Hz, J2 = 9.7 Hz, 1H), 4.8 (d, J = 7.5 Hz, 1H), 7.14–7.32
(m, 15H), 7.46–7.50 (m, 5H) ppm. DEPTQ NMR (100 MHz, CDCl3):
d 24.7 (CH2), 26.6 (CH2), 30.4 (CH3), 48.8 (CH), 51.4 (CH2), 61.1
(CH2), 68.5 (CH), 126.9 (CH), 127.7 (CH), 128.5 (CH), 128.9 (CH),
144.0 (C) ppm; IR 3058, 3026, 2925, 1687, 1490, 1445, 1055,
1238, 1064, 985, 760, 745, 695 cmꢀ1; ½a D20
¼ þ35:8 (c 0.45, CDCl3);
ꢂ
HRMS (ESI+ve) calcd for C30H31NOSꢃH+ 454.2205, found 454.2223.
4.1.5. Synthesis of (S)-(1S,2R)-3-methoxy-1-phenyl-2-
(piperidin-1-yl)propyl ethanethioate Ac-1ba
The procedure was analogous to the one described for Ac-1aa.
Quantitative yield. 1H NMR (400 MHz, CDCl3): d 1.31 (s, 6H), 2.28
(s, 3H), 2.37–2.46 (m, 2H), 2.50–2.58 (m, 2H), 3.08 (m, 1H), 3.33
(s, 3H), 3.51 (dd, J1 = 5.2 Hz, J2 = 10.0 Hz, 1H), 3.55 (dd, J = 6.7 Hz,
J = 10.0 Hz, 1H), 4.80 (m, J = 7.3 Hz, 5H), 7.18–7.33 (m, 5H) ppm;
DEPTQ NMR (100 MHz, CDCl3): d 24.6 (CH2), 26.6 (CH2), 30.5
(CH3), 48.6 (CH), 51.4 (CH2), 58.7 (CH3), 67.8 (CH), 70.7 (CH2),
126.8 (CH), 127.9 (CH), 128.5 (CH), 141.4 (C), 194.8 (C) ppm; IR
3348, 2927, 2850, 2805, 1687, 1451, 1104, 960, 699 cmꢀ1
¼ þ86:8 (c 0.050, CDCl3); HRMS (ESI+ve) calcd for
C17H25NO2SꢃH+ 308.1684, found 308.1682.
;
½ ꢂ
a 2D0
769, 740, 704 cmꢀ1; ½a D20
¼ þ8:2 (c 0.81, CDCl3).
ꢂ
4.1.6. Synthesis of (1S,2R)-3-methoxy-1-phenyl-2-(piperidin-1-
yl)propane-1-thiol 1ba
The procedure was analogous to the one described for 1aa.
Quantitative yield. 1H NMR (400 MHz, CDCl3): d 1.22 (s, 6H),
2.29 (m, 2H), 2.42 (m, 2H), 2.90 (m, 1H), 3.25 (s, 3H), 3.47 (dd,
J1 = 4.6 Hz, J2 = 9.9 Hz, 1H), 3.58 (dd, J1 = 5.9 Hz, J2 = 10.0 Hz,
1H), 4.11 (d, J = 7.5 Hz, 1H), 7.07–7.12 (m, 1H), 7.15–7.19 (m,
2H), 7.21–7.25 (m, 2H) ppm; DEPTQ NMR (100 MHz, CDCl3): d
24.7 (CH2), 26.5 (CH2), 51.3 (CH2), 56.0 (CH), 58.7 (CH3), 66.5
(CH), 71.0 (CH2), 126.6 (CH), 127.5 (CH), 129.3 (CH), 140.8 (C)
ppm; IR 3059, 3026, 2927, 2803, 1702. 1597, 1452, 1309,
4.1.2. Synthesis of (1S,2R)-1-phenyl-2-(piperidin-yl)-3-
(trityloxy)propane-1-thiol 1aa
In a flame-dried, round-bottomed flask, Ac-1aa was weighed
(147 mg, 0.27 mmol) and dissolved in anhydrous diethyl ether
(2.5 mL under argon. The solution was cooled to ꢀ78 °C and 1 M
DIBALH in hexane (0.58 mL 0.58 mmol) was added dropwise. The
reaction mixture was allowed to warm up to rt, and stirred for a
further 5 h. Then it was cooled again at ꢀ78 °C, and methanol
(2.5 mL was added dropwise. When the solution reached room
temperature the solvent was evaporated under vacuum. The crude
1271, 1202, 1166, 745, 698 cmꢀ1; ½a D20
¼ þ179:7 (c 0.27, CDCl3);
ꢂ

S. Subirats et al. / Tetrahedron: Asymmetry 20 (2009) 1413–1418
1417
HRMS (ESI+ve) calcd for C15H23NOSꢃH+ 266.1579, found
amine pre-treated silica gel (2.5% v/v), eluting with hexane:AcOEt
mixtures of increasing polarity. Quantitative yield. 1H NMR
(400 MHz, CDCl3): d 1.33 (m, 3H), 1.43 (m, 3H), 2.34 (m, 4H),
3.02 (dd, J1 = 6.1 Hz, J2 = 11.7 Hz, 1H), 3.16 (dd, J1 = 6.7 Hz,
J2 = 9.8 Hz, 1H), 3.26 (dd, J1 = 6.2 Hz, J2 = 9.8 Hz, 1H), 4.88 (d,
J = 5.3 Hz, 1H), 7.23–7.44 (m, 15H) ppm; DEPTQ NMR (100 MHz,
CDCl3): d 24.4 (CH2), 26.7 (CH2), 52.5 (CH2), 69.0 (CH), 71.1 (CH),
126.0 (CH), 127.1 (CH), 127.8 (CH), 128.6 (CH), 143.8 (C) ppm; IR
3375, 3057, 3026, 2929, 1597, 1490, 1447, 1060, 1031, 745,
266.1569.
4.1.7. Synthesis of (S)-(1S,2R)-2-(dimethylamino)-3-methoxy-1-
phenylpropyl ethanethioate Ac-1bb
The procedure was analogous to the one described for Ac-1aa.
Yield = 98%. 1H NMR (400 MHz, CDCl3): d 2.29 (s, 3H), 2.30 (s,
6H), 3.04 (dd, J1 = 5.8 Hz, J2 = 11.2 Hz, 1H), 3.32 (s, 3H), 3.50 (m,
2H), 4.90 (d, J = 6.8 Hz, 1H), 7.20–7.36 (m, 5H) ppm; DEPTQ NMR
(100 MHz, CDCl3): d 30.5 (CH3), 42.2 (CH3), 47.7 (CH), 58.8 (CH3),
67.3 (CH), 70.0 (CH2), 127.1 (CH), 128.3 (CH), 128.3 (CH) ppm; IR
3060, 3027, 2922, 2871, 2827, 2780, 1686, 1451, 1353, 1278,
697 cmꢀ1; ½a 2D0
¼ þ3:1 (c 0.84, CDCl3); HRMS (ESI+ve) calcd for
ꢂ
C33H35NO2.H+ 478.2757, found 478.2746.
1187, 1115, 953, 767, 728, 697 cmꢀ1; ½a D20
ꢂ
¼ þ226:3 (c 0.053,
4.1.11. Synthesis of (1S,2R)-2-(dimethylamino)-1-phenyl-3-
(trityloxy)propyl 4-nitrobenzoate PNB-2ab
CDCl3); HRMS (ESI+ve) calcd for C14H21NO2S.Na+ 290.1191, found
290.1178.
The procedure was analogous to the one described for PNB-2aa.
Yield = 55%. 1H NMR (400 MHz, CDCl3): d 2.30 (s, 3H), 3.37 (m, 1H),
3.42–3.48 (m, 1H), 3.49–3.55 (m, 1H), 6.17 (d, J = 6.6 Hz, 1H), 7.16–
7.33 (m, 15H), 7.34–7.40 (m, 5H), 7.97 (m, 2H), 8.16 (m, 2H) ppm;
DEPTQ NMR (100 MHz, CDCl3): d 42.3 (CH3), 60.1 (CH2), 68.0 (CH),
76.1 (CH), 123.5 (CH), 126.8 (CH), 127.1 (CH), 127.8 (CH), 128.1
(CH), 128.5 (CH), 128.7 (CH), 128.8 (CH), 130.8 (CH), 135.5 (C),
139.1 (C), 143.9 (C), 150.5 (C), 163.5 (C) ppm; IR 3057, 3031,
2934, 2830, 2782, 2324, 1724, 1604, 1525, 1490, 1269, 1100,
4.1.8. Synthesis of (1S,2R)-2-(dimethylamino)-3-methoxy-1-
phenylpropane-1-thiol 1bb
The procedure was analogous to the one described for 1aa.
Yield = 50%. 1H NMR (400 MHz, CDCl3): d 2.16 (s, 6H), 2.93–2.97
(m, 1H), 3.24 (s, 3H), 3.56 (dd, J1 = 3.6 Hz, J2 = 10.2 Hz, 1H), 3.60
(dd, J1 = 5.8 Hz, J2 = 10.2 Hz, 1H), 4.19 (d, J = 7.9 Hz, 1H), 7.14–
7.29 (m, 5H) ppm. DEPTQ NMR (100 MHz, CDCl3): d 41.8 (CH3),
55.2 (CH), 58.7 (CH3), 65.6(CH), 70.2(CH2), 127.0 (CH), 128.0
(CH), 129.2 (CH), 140.7 (C) ppm; IR 2922, 1453, 1377, 1279,
762, 697 cmꢀ1; ½a D20
¼ þ1:51 (c = 0.057, CHCl3); HRMS (ESI+ve)
ꢂ
calcd for C37H34N2O5.Na+ 609.2352, found 609.2365.
1120, 697 cmꢀ1; ½a D20
¼ þ97:7 (c 3.4, CDCl3); HRMS (ESI+ve) calcd
ꢂ
for C12H19NSO.H+ 226.1266, found 226.1270.
4.1.12. Synthesis of (1S,2R)-2-(dimethylamino)-1-phenyl-3-
(trityloxy)propan-1-ol 2ab
4.1.9. Synthesis of (1S,2R)-1-phenyl-2-(piperidin-1-yl)-3-
(trityloxy)propyl 4-nitrobenzoate PNB-2aa
The procedure was analogous to the one described for 2aa.
Yield = 98%. 1H NMR (400 MHz, CDCl3): d 2.24 (s, 6H), 2.97 (dd,
J1 = 5.4 Hz, J2 = 10.7 Hz, 1H), 3.20 (dd, J1 = 5.9 Hz, J2 = 10.2 Hz,
1H), 3.29 (dd, J1 = 5.3 Hz, J2 = 10.3 Hz, 1H), 4.95 (d,
J = 4.7 Hz,1H), 7.20–7.28 (m, 14H), 7.36–7.39 (m, 6H) ppm;
DEPTQ NMR (100 MHz, CDCl3): d 43.4(CH3), 60.4 (CH2), 68.9
(CH), 72.0 (CH), 126.1 (CH), 127.1 (CH), 127.8 (CH), 128.6 (CH),
143.6 (C) ppm; IR 3057, 3024, 2932, 2873, 2827, 2781, 2361,
In a flame-dried flask, (1R,2R)-1-phenyl-1-(piperidin-1-yl)-3-
(trityloxy)propan-2-ol (1.3 g, 2.72 mmol) was dissolved in anhy-
drous dichloromethane (30 mL under argon. At 0 °C triethylamine
(1.26 mL 8.99 mmol) and methanesulfonyl chloride (0.34 mL
4.36 mmol) were added and the mixture was stirred at that tem-
perature. After 2 h, p-nitrobenzoic acid (4.0 g, 15.25 mmol) and
NaOH (0.61 g, 15.25 mmol) dissolved in water (90 mL were added.
After 20 min, the ice bath was removed and the mixture was al-
lowed to react overnight at room temperature. The reaction mix-
ture was quenched with water and extracted with
dichloromethane (50 mLꢁ 3). The combined organic layers were
washed with hydrochloric acid (0.04 % v/v in water) and saturated
aqueous solution of NaHCO3, and dried over anhydrous sodium
sulfate. The solvent was removed under vacuum. The crude prod-
uct was purified by flash chromatography on triethylamine pre-
treated silica gel (2.5% v/v), with hexane and ethyl acetate mixtures
as eluent. 61% yield. 1H NMR (400 MHz, CDCl3): d1.38–1.50 (m,
6H), 2.56–2.64 (m, 2H), 2.69–2.76 (m, 2H), 3.43 (m, 1H), 3.56
(dd, J1 = 3.9 Hz, J2 = 9.8 Hz, 1H), 3.63 (dd, J1 = 6.5 Hz, J2 = 9.8 Hz,
1H), 6.26 (d, J = 7.0 Hz, 1H), 7.25–7.46 (m, 14H), 7.53–7.57 (m,
6H), 8.08–8.11 (m, 2H), 8.25–8.28 (m, 2H) ppm; IR 3027, 2971,
2933, 2801, 1721, 1603, 1527, 1490, 1445, 1316, 1271, 1109,
905, 698 cmꢀ1; HRMS (ESI+ve) calcd for C40H38N2O5.H+ 627.2859,
found 627.2885.
1596, 1489, 1447, 1057, 1031, 745, 696 cmꢀ1; ½a D20
¼ þ35:8 (c
ꢂ
0.45, CHCl3); HRMS (ESI+ve) calcd for C30H31NO2.H+ 438.2453,
found 438.2433.
4.1.13. Synthesis of (1S,2R)-2-(dimethylamino)-3-methoxy-1-
phenylpropyl 4-nitrobenzoate PNB-2bb
The procedure was analogous to the one described for PNB-2aa.
Yield = 69%. 1H NMR (400Mhz, CDCl3): d 2.40 (s, 3H), 3.22–3.26 (m,
1H), 3.30 (s, 3H), 3.66 (dd, J1 = 3.6 Hz, J2 = 10.2 Hz 1H), 3.77 (dd,
J1 = 7.3 Hz, J2 = 10.2 Hz, 1H), 6.29 (d, J = 5.5 Hz, 1H), 7.26–7.31 (m,
1H), 7.33–7.40 (m, 4H), 8.24–8.26 (m, 2H), 8.30–8.32 (m, 2H)
ppm; DEPTQ NMR (100 MHz, CDCl3): d 41.8 (CH3), 59.0 (CH3),
67.7 (CH), 68.7 (CH2), 74.8 (CH), 123.7 (CH), 126.4 (CH), 128.0
(CH), 128.5 (CH), 130.8 (CH), 135.6 (C), 139.0 (C), 150.7 (C), 163.5
(C) ppm; IR 3032, 2871, 2829, 2783, 1723, 1606, 1525, 1454,
1344, 1268, 1100, 1014, 974, 872, 719, 699 cmꢀ1; ½a D20
¼ ꢀ53:8 (c
ꢂ
0.05, CHCl3); HRMS (ESI+ve) calcd for C19H22N2O5.Na+ 381.1426,
found 381.1429.
4.1.14. Synthesis of (1S,2R)-2-(dimethylamino)-3-methoxy-1-
phenylpropan-1-ol 2bb
4.1.10. Synthesis of (1S,2R)-1-phenyl-2-(piperidin-1-yl)-3-
(trityloxy)propan-1-ol 2aa
The procedure was analogous to the one described for 2aa.
Yield = 82%. 1H NMR (400 MHz, CDCl3): d 2.43 (s, 6H), 2.68 (dd,
J1 = 4.6 Hz, J2 = 9.7 Hz, 1H), 3.28 (s, 3H), 3.40 (dd, J1 = 5.3 Hz,
J2 = 10.1 Hz, 1H), 3.47 (dd, J1 = 4.2 Hz, J2 = 10.2 Hz, 1H), 5.01 (d,
J = 4.5 Hz, 1H), 7.25–7.26 (m, 1H), 7.34–7.36 (m, 4H) ppm; DEPTQ
NMR (100 MHz, CDCl3): d 43.2 (CH3), 58.9 (CH3), 68.5 (CH), 69.8
(CH2), 72.5 (CH), 125.9 (CH), 127.0 (CH), 128.1 (CH) ppm; IR
3058, 2983, 2919, 2892, 2870, 2834, 2808, 2780, 1446, 1317,
In a flame-dried round-bottomed flask flushed with nitrogen,
sodium methoxide (0.75 g, 13.19 mmol) was dissolved in 150 mL
of methanol and transferred via cannula to another flask containing
PNB-2aa (1.38 g, 2.20 mmol) in 15 mL of dichloromethane, at rt.
After 30 minutes, the reaction mixture was treated with brine
and the product was extracted with dichloromethane (x3). The
combined organic layers were dried with anhydrous sodium sul-
fate and concentrated under vacuum, affording an orange oil. The
crude product was purified by flash chromatography on triethyl-
1259, 1242, 1203, 1109, 1079, 1058, 951, 777, 684 cmꢀ1
;

1418
S. Subirats et al. / Tetrahedron: Asymmetry 20 (2009) 1413–1418
3. Review on asymmetric alkynylzinc additions: Pu, L. Tetrahedron 2003, 59, 9873.
½
a 2D0
ꢂ
¼ þ16:7 (c 0.55, CDCl3); HRMS (ESI+ve) calcd for
4. Braga, A. L.; Appelt, H. R.; Silveira, C. C.; Wessjohann, L. A.; Schneider, P. H.
Tetrahedron 2002, 58, 10413.
C12H19NO2.H+ 210.1503, found 210.1494.
5. (a) Wipf, P.; Ribe, S. J. Org. Chem. 1998, 63, 6454; (b) Wipf, P.; Jayasuriya, N.
Chirality 2008, 20, 425.
6. (a) Vidal-Ferran, A.; Moyano, A.; Pericàs, M. A.; Riera, A. J. Org. Chem. 1997, 62,
4970; (b) Vidal-Ferran, A.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron Lett.
1997, 38, 8773; (c) Jimeno, C.; Pastó, M.; Pericàs, M. A.; Riera, A. J. Org. Chem.
2003, 68, 3130.
4.1.15. Typical procedure for the asymmetric alkynylation of
aldehydes: synthesis of (R)-1,3-diphenylprop-2-yn-1-ol
Dimethylzinc (4 mmol, 2 mL of 2 M solution in toluene) was
added to a freshly distilled phenylacetylene (4 mmol, 0.44 mL solu-
tion in diethyl ether (12 mL, and the reaction mixture was stirred
at 50 °C for 1 h. Then, the resulting solution was cooled to 0 °C,
and the ligand (0.049 mmol) was added and stirred at 0 °C for
1 h. Finally, freshly distilled benzaldehyde (1 mmol) was added
and the solution reacted for 4 h at 0 °C. The reaction mixture was
then cautiously quenched with aq satd NH4Cl (5 mL) and extracted
with dichloromethane (3 ꢁ 5 mL). The combined organic extracts
were dried over anhydrous Na2SO4. The residue obtained after
evaporation of the solvent was purified by flash chromatography.
1H NMR (400 MHz, CDCl3): d 2.31 (s, 1H), 5.61 (s, 1H), 7.21–7.32
(m, 6H), 7.4 (m, 2H), 7.50 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
d 65.1 (CH), 86.6 (C), 88.7 (C), 122.4 (CH), 126.7 (CH), 128.3 (CH),
128.4 (CH), 128.6 (CH), 128.6 (CH), 140.9 (C) ppm; IR 3350, 3059,
3028, 2928, 2197, 1697, 1597, 1313, 1033, 960, 912, 821, 756,
692 cmꢀ1; HPLC: Daicel CHIRALCEL-OD. Hexane/i-PrOH 90:10,
1.0 mL/min, k = 254 nm, tR(R) = 12.0 min (major), tR(S) = 17.9 min;
HRMS (ESI+ve) calcd for C15H12OꢃNa+, 231.08, found 231.0868.
7. For modular amino alcohols and their application in organozinc chemistry, see:
(a) Rodríguez-Escrich, S.; Solà, L.; Jimeno, C.; Rodríguez-Escrich, C.; Pericàs, M.
A. Adv. Synth. Catal. 2008, 350, 2250; (b) Rodríguez-Escrich, S.; Reddy, K. S.;
Jimeno, C.; Colet, G.; Rodríguez-Escrich, C.; Solà, L.; Vidal-Ferran, A.; Pericàs, M.
A. J. Org. Chem. 2008, 73, 5340; (c) Jimeno, C.; Sayalero, S.; Fjermestad, T.; Colet,
G.; Maseras, F.; Pericàs, M. A. Angew. Chem., Int. Ed. 2008, 47, 1098; (d) García-
Delgado, N.; Reddy, K. S.; Solà, L.; Riera, A.; Pericàs, M. A.; Verdaguer, X. J. Org.
Chem. 2005, 70, 7426; (e) García-Delgado, N.; Fontes, M.; Pericàs, M. A.; Riera,
A.; Verdaguer, X. Tetrahedron: Asymmetry 2004, 15, 2085; (f) Fontes, M.;
Verdaguer, X.; Solà, L.; Pericàs, M. A.; Riera, A. J. Org. Chem. 2004, 69, 2532; (g)
Fontes, M.; Verdaguer, X.; Solà, L.; Vidal-Ferran, A.; Reddy, K. S.; Riera, A.;
Pericàs, M. A. Org. Lett. 2002, 4, 2381; (h) Jimeno, C.; Reddy, K. S.; Solà, L.;
Moyano, A.; Pericàs, M. A.; Riera, A. Org. Lett. 2000, 2, 3157; (i) Jimeno, C.; Vidal-
Ferran, A.; Moyano, A.; Pericàs, M. A.; Riera, A. Tetrahedron Lett. 1999, 40, 777;
(j) Reddy, K. S.; Solà, L.; Moyano, A.; Pericàs, M. A.; Riera, A. J. Org. Chem. 1998,
64, 3969; (k) Solà, L.; Reddy, K. S.; Vidal-Ferran, A.; Moyano, A.; Pericàs, M. A.;
Riera, A.; Alvarez-Larena, A.; Piniella, J.-F. J. Org. Chem. 1998, 63, 7078.
8. Jimeno, C.; Vidal-Ferran, A.; Pericàs, M. A. Org. Lett. 2006, 8, 3895.
9. Jimeno, C.; Moyano, A.; Pericàs, M. A.; Riera, A. Synlett 2001, 1155.
10. (a) Okhlobystin, O. Y.; Zakharkin, L. I. J. Organomet. Chem. 1965, 3, 257; (b)
Cozzi, P. G.; Rudolph, J.; Bolm, C.; Norrby, P.-O.; Tomasini, C. J. Org. Chem. 2005,
70, 5733.
11. Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990, 937.
12. Selected recent examples: (a) Wang, M.-C.; Zhang, Q.-J.; Zhao, W.-X.; Wang,
X.-D.; Ding, X.; Jing, T.-T.; Song, M.-P. J. Org. Chem. 2008, 73, 168; (b) Li, H.;
Huang, Y.; Jin, W.; Xue, F.; Wan, B. Tetrahedron Lett. 2008, 49, 1686; (c)
Li, Z.-B.; Liu, T.-D.; Pu, L. J. Org. Chem. 2007, 72, 4340; (d) Liebehentschel, S.;
Cvengros, J.; von Wangelin, A. J. Synlett 2007, 2574; (e) Wang, Q.; Chen, S.-Y.;
Yu, X.-Q.; Pu, L. Tetrahedron 2007, 63, 4422; (f) Wang, Q.; Zhang, B.
Hu, G.; Chen, C.; Zhao, Q.; Wang, R. Org. Biomol. Chem. 2007, 5, 1161; (g)
Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J. R. J. Org. Chem. 2006,
71, 6674; (h) Scarpi, D.; Lo Galbo, F.; Guarna, A. Tetrahedron: Asymmetry 2006,
17, 1409; (i) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc.
2006, 128, 8; (j) Pizzuti, M. G.; Superchi, S. Tetrahedron: Asymmetry 2005, 16,
2263; (k) Mao, J.; Wan, B.; Wu, F.; Lu, S. Chirality 2005, 17, 245; (l) Dahmen, S.
Org. Lett. 2004, 6, 2113; (m) Li, Z.-B.; Pu, L. Org. Lett. 2004, 6, 1065; (n) Gao,
G.; Xie, R.-G.; Pu, L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5417; (o) Kang, Y.-K.;
Liu, L.; Wang, R.; Yan, W.-J.; Zhou, Y.-F. Tetrahedron: Asymmetry 2004, 15,
3155.
Acknowledgments
This work was funded by MICINN (Grant CTQ2008–00947/
BQU), DIUE (Grant 2005SGR225), Consolider Ingenio 2010 (Grant
CSD2006-0003), and ICIQ Foundation.
References
1. Reviews on chiral sulfur-containing ligands: (a) Mellah, M.; Voituriez, A.;
Schulz, E. Chem. Rev. 2007, 107, 5133; (b) Pellissier, H. Tetrahedron 2007, 63,
1297.
2. Kang, J.; Kim, J. B.; Kim, J. W.; Lee, D. J. Chem. Soc., Perkin Trans. 1997, 2, 189. For
related work on arylations using aminothioacetates, see: Jin, M.-J.; Sarkar, S.M.;
Lee, D.-H.; Qiu, H. Org. Lett. 2008, 10, 1235.
13. Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116, 3151.