Enantioselective Morita-Baylis-Hillman reaction promoted by l-threonine-derived phosphine-thiourea catalysts

Article abstract of DOI:10.1039/c1ob05881a

A series of bifunctional phosphine-thiourea organic catalysts based on natural amino acid scaffolds were designed and prepared. l-Threonine-derived bifunctional phosphine catalysts were found to be very efficient in promoting asymmetric Morita-Baylis-Hillman (MBH) reaction of acrylates with aromatic aldehydes, affording the desired MBH adducts with up to 90% ee. To gain mechanistic insights into the reaction, the effects of adding various additives on the MBH reaction were investigated. We propose that the hydrogen bonding interactions between the thiourea moiety of the catalyst and the enolate intermediate are crucial for the stereochemical outcome of the reaction. The method described in this report may provide a practical solution to the enantioselective MBH reaction of simple acrylates.

Full text of DOI:10.1039/c1ob05881a

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PAPER
Enantioselective Morita–Baylis–Hillman reaction promoted by
L-threonine-derived phosphine–thiourea catalysts†
Xiaoyu Han,a Youqing Wang,b Fangrui Zhonga and Yixin Lu*a
Received 2nd June 2011, Accepted 12th July 2011
DOI: 10.1039/c1ob05881a
A series of bifunctional phosphine–thiourea organic catalysts based on natural amino acid scaffolds
were designed and prepared. L-Threonine-derived bifunctional phosphine catalysts were found to be
very efficient in promoting asymmetric Morita–Baylis–Hillman (MBH) reaction of acrylates with
aromatic aldehydes, affording the desired MBH adducts with up to 90% ee. To gain mechanistic insights
into the reaction, the effects of adding various additives on the MBH reaction were investigated. We
propose that the hydrogen bonding interactions between the thiourea moiety of the catalyst and the
enolate intermediate are crucial for the stereochemical outcome of the reaction. The method described
in this report may provide a practical solution to the enantioselective MBH reaction of simple acrylates.
Introduction
Trivalent phosphines, traditionally utilized as ligands in transition
metal mediated processes, have recently emerged as versatile
Lewis base catalysts in synthetic organic chemistry.1 As a sig-
nificant complement to the amine-based catalysts, phosphines
often display remarkable and unique properties in nucleophilic
catalysis due to their weaker basicity and stronger nucleophilicity.
Compared with the extensive studies carried out on phosphine-
triggered organic transformations, the development of efficient
and versatile chiral phosphine catalysts and their applications in
enantioselective organic reactions remain a less-explored research
area.2 As part of our continuous efforts toward the evolution of
amino acid-derived organic catalysts for enantioselective organic
transformations,3 we recently embarked on an exciting journey
of exploring novel bifunctional chiral phosphines derived from
amino acid structural scaffolds (Fig. 1). We showed that novel
chiral phosphines bearing dipeptidic backbones could efficiently
Fig. 1 Applications of amino acid-derived bifunctional phosphines in
promote the enantioselective [3 + 2] cycloaddition of allenoates
with acrylates, affording functionalized cyclopentenes in excel-
lent chemical yields and with very high enantioselectivities.2p
Subsequently, we demonstrated acrylamides were suitable sub-
strates in asymmetric [3 + 2] cycloaddition.2q Very recently, we
derived a series of phosphine–sulfonamide bifunctional catalysts
and demonstrated their effectiveness in the enantioselective aza-
Morita–Baylis–Hillman (MBH) reaction.3l It is thus highly desir-
(aza)-MBH reactions.
able to further extend the utility of amino acid-based phosphine
catalysts to other important organic reactions.
The MBH reaction is one of the most valuable carbon–carbon
bond-forming reactions, which provides easy access to heavily
functionalized and synthetically useful MBH adducts from readily
available activated olefins and aldehydes.4 In the past decade,
the development of enantioselective versions of MBH reactions
has received increasing attention from the synthetic community.
Among the activated alkenes suitable for MBH reactions, enones
are most commonly employed; a number of elegant asymmet-
ric MBH reactions between enones and aldehydes have been
developed in the past few years.5 On the other hand, examples
using acrylates as a reaction partner in highly enantioselective
MBH reactions are very limited.6 In 1999, Hatakeyama and
aDepartment of Chemistry & Medicinal Chemistry Program, Life Sciences
Institute, National University of Singapore, 3 Science Drive 3, Singapore,
117543, Republic of Singapore. E-mail: chmlyx@nus.edu.sg; Fax: +65-
6779-1691; Tel: +65-6516-1569
bProvincial Key Laboratory of Natural Medicine and Immuno-Engineering,
Henan University, Jinming Campus, Kaifeng, Henan, 475004, P.R. China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob05881a
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co-workers disclosed a highly enantioselective MBH reaction
between hexafluoroisopropyl acrylate (HFIPA) and aldehydes,
catalyzed by a novel quinine-derived b-isocupreidine (b-ICD).7
Although HFIPA had to be employed, and the chemical yields
were modest in many cases, nevertheless, the Hatakeyama method
represented a breakthrough in the field; highly enantioselective
MBH reaction of acrylates was shown to be feasible.8 Recently,
there have been a few reports on organocatalytic enantioselective
MBH reactions between aldehydes and acrylates.9 These methods,
however, suffered from limited substrate scope, moderate yields
or low enantioselectivities. There clearly exists a need for an
enantioselective MBH reaction in which simple acrylates can be
used directly. Herein, we describe the development of amino acid-
derived phosphine–thiourea catalysts, and their applications in
enantioselective MBH reaction between aromatic aldehydes and
simple acrylates.
Scheme
catalysts.
2
Preparation of L-threonine-derived phosphine–thiourea
intermediates are stable in the air at room temperature, and have
a shelf life of at least a few months.
The MBH reaction between p-nitrobenzaldehyde and methyl
acrylate was chosen as a model reaction to evaluate the ef-
fectiveness of our phosphine catalysts (Table 1). L-Valine-based
bifunctional phosphines with different Brønsted acid moieties
were tested first to establish the influence of Brønsted acids
on the reaction. Phosphine–sulfonamides 1a and 1b displayed
high reactivity, however, the enantioselectivity was disappointing
(entries 1–2). Phosphine 2 containing a Boc group led to the
formation of the desired product with moderate ee (entry 3).
Dipeptide-derived phosphine–thioureas 3a and 3b turned out
to be quite good catalysts, and the MBH adducts were formed
in high yields and with good enantioselectivities (entries 4–5).
The thiourea moieties in the catalysts seemed important in the
asymmetric induction, thus, a number of phosphines bearing
different aryl thioureas (catalysts 4a–4j) were next prepared and
screened (entries 6–15), and it was found the p-F-phenyl-thiourea
moiety was most efficient in chiral induction (entry 11, 85% yield,
83% ee). Having established the importance of steric effects in
Results and discussion
Amino acids serve as an excellent starting point for derivatizing
various bifunctional chiral phosphine catalysts. The phosphine
group in the catalysts is derived from the carboxylic acid via
simple functional group transformations. Moreover, the presence
of a neighbouring primary alkyl carbon makes the phosphorus
center highly nucleophilic, as we demonstrated in our previous
reports.2p,q,3l By installing different Brønsted acid moieties at the
amino sites, and selecting valine or threonine as the chiral back-
bone, a number of bifunctional phosphine catalysts were prepared
(Scheme 1). We chose to prepare L-threonine-based phosphine
catalysts, since the effectiveness of the threonine motif in stere-
ochemical control has been amply demonstrated by us.2p,q,3b–d,3g,3l
The isopropyl group in valine serves as a convenient gauge for
evaluating steric effects in the asymmetric induction, and the
preparation of valine-based catalysts is also more straightforward.
Table 1 Screening of amino acid-based bifunctional phosphines in the
MBH reactiona
Entry
Cat.
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
2
88
92
67
85
70
89
90
83
80
84
85
88
91
78
81
90
78
88
79
40
37
53
79
72
80
76
80
77
77
83
79
78
77
69
85
85
84
84
3a
3b
4a
4b
4c
4d
4e
4f
9
10
11
12
13
14
15
16
17
18
19
Scheme 1 Amino acid-derived bifunctional phosphines.
4g
4h
4i
Preparation of bifunctional phosphine–thiourea catalysts from
L-threonine is illustrated in Scheme 2. Following the literature
procedure,10 threonine was protected as an oxazolidine 6. The
hydroxy group was converted to a mesylate, and a substitution
reaction with NaPPh2 introduced the phosphine moiety into
the catalyst. Acidic treatment yielded phosphine 8 with the
free amino group, which smoothly reacted with thioisocyanate
to afford the advanced intermediate 9. Finally, silylation gave
phosphine–thiourea catalysts 5a to 5d. It is noteworthy that the
above phosphine catalysts and phosphorus-containing synthetic
4j
5a
5b
5c
5d
a The reaction was performed with 10a (0.1 mmol), 11a (0.15 mmol) and
the catalyst (0.01 mmol) in anhydrous THF (0.2 mL) under N2 at room
temperature for 24 h. b Isolated yield. c Determined by HPLC analysis on
a chiral stationary phase.
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Table 2 Solvent screening for 5a-catalyzed MBH reactiona
Table 3 Employment of different acrylates in the MBH reactiona
Yield (%)b
ee (%)c
Entry
Solvent
Yield (%)b
ee (%)c
Entry
R
1
2
3
4
5
6
7
8
THF
90
88
49
45
48
25
24
32
36
15
85
92
84
85
82
65
42
61
45
45
51
13
39
87
87
86
1
2
3
4
5
6
Me
Et
Bn
t-Bu
Ph
1-naphthyl
92
92
94
84
trace
32
87
85
84
82
—
11
1,4-Dioxane
Toluene
CH2Cl2
Ether
CH3CN
DMSO
DMF
MeOH
THF/H2O (4/1)
THF
d
a The reaction was performed with 10a (0.1 mmol), 11a (0.15 mmol) and
˚
9
5a (0.01 mmol) in anhydrous THF (0.4 mL) containing 4 A molecular
sieves (50 mg) under N2 at room temperature for 24 h. b Isolated yield.
c Determined by HPLC analysis on a chiral stationary phase. d Not
determined.
10
11d
12e
13f
THF
THF
a The reaction was performed with 10a (0.1 mmol), 11a (0.15 mmol) and 5a
Table 4 Substrate scope of 5a-catalyzed MBH reactiona
(0.01 mmol) in anhydrous THF (0.2 mL) under N2 at room temperature for
24 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary
e
phase. d 0.4 mL THF was used. 4 A molecular sieves were added. f The
˚
reaction was performed at 10 ◦C for 72 h.
Entry
x
t (h)
Product (R)
Yield (%)b
ee (%)c
asymmetric induction with valine-derived phosphines, we then
focused on derivatization of phosphine–thiourea catalysts (5a–
5d) based on threonine backbone. Very similar reactivities and
selectivities were observed with different silyloxy groups (entries
16–19); the catalyst with the TBS group (5a) was chosen for further
studies as it gave slightly better results than the other silyloxy-
containing catalysts, and its preparation was more economical.
The influence of different solvents on 5a-catalyzed MBH
reaction was next investigated, and the results are summarized
in Table 2. 1,4-Dioxane was found to be a suitable solvent,
offering slightly inferior results to those obtained with THF
(entry 2). All the other common organic solvents were shown
to be unsuitable, affording products in low yields and with poor
enantioselectivities (entries 3–8). A protic solvent, e.g. methanol,
proved to be an extremely poor medium, and the desired MBH
adduct was obtained in 36% yield and with only 13% ee (entry
9). This result seemed to suggest hydrogen bonding interactions
might be very important in stereochemical control, as methanol
likely disrupted such key interactions. When a THF/water solvent
pair was employed, a very low yield and poor enantioselectivity
were observed, contrasting with the excellent results attainable
using THF alone as the solvent. Under the optimized reaction
conditions in which molecular sieves were added, the MBH adduct
was obtained in 92% yield and 87% ee (entry 12).
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
20
20
20
20
20
20
20
20
20
20
20
20
24
24
36
36
40
40
40
60
60
60
60
60
72
96
96
72
72
72
96
12b (3-NO2-Ph)
12c (2-NO2-Ph)
12d (4-CN-Ph)
12e (3-CN-Ph)
12f (4-CF3-Ph)
12g (3,5-CF3-Ph)
12h (3-NO2-2-Cl-Ph)
12i (4-F-Ph)
84
91
92
89
80
74
89
72
67
63
73
77
43
25
27
53
87
52
85
69
87
85
87
84
85
81
84
82
83
84
80
76
77
90
84
70
—
9
12j (4-Cl-Ph)
10
11
12
13
14
15
16
17
18
19
12k (3-Cl-Ph)
12l (4-Br-Ph)
12m (3-Br-Ph)
12n (Ph)
12o (4-Me-Ph)
12p (3-Me-Ph)
12q (2-naphthyl)
12r (3-pyridine)
12s (2-thiophenyl)
12t (CH2Ph)
d
—
a The reaction was performed with 10 (0.1 mmol), 11a (0.15 mmol for
entries 1–7 and 0.2 mmol for entries 8–19) and 5a in anhydrous THF
(0.4 mL for entries 1–12 and 0.2 mL for entries 13–19) containing
4 A molecular sieves under N2 at room temperature. b Isolated yield.
˚
c Determined by HPLC analysis on a chiral stationary phase. d No
reaction.
aldehydes with various electron-withdrawing groups at different
positions of the aryl ring, and high yields and enantioselectivities
were generally attainable (entries 1–7). In contrast to the related
examples in the literature in which virtually only electron-poor
aldehydes could be utilized,7–9 our reaction was applicable to a wide
range of aryl aldehydes. The reaction worked well for the halo-
genated aromatic aldehydes and benzaldehyde, and consistently
high enantioselectivities were achieved (entries 8–13). Moreover,
electron-rich aromatic aldehydes could be employed as well,
and the reactions proceeded with good enantioselectivities, even
though the chemical yields were poor (entries 14–15). In addition,
aromatic aldehydes bearing naphthyl or heterocyclic rings were
also found to be suitable (entries 16–18). However, aliphatic
With the best catalyst and the most appropriate solvent in hand,
we next examined different acrylates in the 5a-catalyzed MBH
reaction (Table 3). Simple alkyl acrylates gave best results, excellent
yields and enantioselectivities were attainable (entries 1–4); the
enantioselectivity seemed to be dependent on the steric hindrance
of the ester group, and the most sterically hindered t-butyl acrylate
led to decreased enantioselectivity compared with less hindered
acrylates. The aryl acrylates, on the other hand, were found to be
unsuitable for the reaction (entries 5–6).
The substrate scope for 5a-catalyzed MBH reactions was next
investigated (Table 4). The reaction is applicable to aromatic
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Table 5 Examination of the effects of various additives on 5a-catalyzed
MBH reactiona
Entry
Additive
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
none
MeOH (10 mol%)
13 (10 mol%)
13 (20 mol%)
13 (50 mol%)
13 (100 mol%)
PhOH (10 mol%)
2-Naphthol (10 mol%)
PhCOOH (10 mol%)
PhCOOH (20 mol%)
TFA (10 mol%)
92
93
90
89
86
81
84
88
37
87
84
85
85
84
83
77
74
85
—
—
Scheme 3 Proposed mechanism for phosphine–thiourea 5a-promoted
MBH reaction.
strong intramolecular hydrogen bonding interactions3l,7,14 between
thiourea and the enolate facilitate the formation of a structurally
well-defined intermediate A, which reacts with the aldehyde sub-
strate in a highly stereochemically selective manner, accounting for
the high enantioselectivity observed. This proposal is supported
by the results obtained with the additive studies. Relatively weak
external hydrogen bond donors competed unfavourably with the
intramolecular thiourea in their interactions with the enolate, and
thus had no significant influence on the enantioselectivity (Table 5,
entries 2–6). Stronger hydrogen bond donors disrupted thiourea–
enolate interaction more, resulting in decreased enantioselectivity
(Table 5, entries 7–8). The addition of carboxylic acids, such as
benzoic acid or TFA, may partially/completely protonate the
enolate intermediate A, thus leading to a marked decrease in
chemical yield or a complete stop of the reaction. Had the external
proton donors participated in the proton transfer step, a more
dramatic decrease in enantioselectivity would be anticipated, as
we had observed in a related study.14
9
10
11
d
—
—
d
a The reaction was performed with 10a (0.1 mmol), 11a (0.15 mmol) and 5a
(0.01 mmol) in anhydrous THF (0.4 mL) under N2 at room temperature for
24 h. b Isolated yield. c Determined by HPLC analysis on a chiral stationary
phase. d No reaction.
aldehydes could not be efficiently activated in our system. It should
be noted that only the desired MBH adducts were observed in
the 5a-catalyzed MBH reactions, undesired dioxanones11 were not
observed under our reaction conditions.
Given the widespread uses of thiourea as the hydrogen bonding
catalyst in asymmetric catalysis,12 a mechanistic proposal involving
hydrogen bonding interactions between the bifunctional phos-
phines and the substrate/intermediates seems to be plausible. We
focused on the potential roles that the thiourea moiety might have
played in our catalytic systems. Toward this end, the effects of
adding various external proton donors on the 5a-catalyzed MBH
reaction were next investigated (Table 5). The presence of methanol
slightly decreased the enantioselectivity of the reaction (entry 2).
The addition of thiourea 13, which mimics the thiourea moiety in
catalyst 5a, did not have much influence on the stereoselectivity
of the reaction, even in a large excess (entries 3–6). However, the
addition of a stronger hydrogen bond donor, phenol or 2-naphthol,
clearly lowered the enantioselectivity of the reaction (entries 7–8).
Interestingly, inclusion of a strong acid in the reaction system, e.g.
benzoic acid, had virtually no effect on the enantioselectivity, but
resulted in a dramatically decreased chemical yield (entry 9). On
the other hand, adding excess benzoic acid, or a much stronger tri-
fluoroacetic acid completely stopped the reaction (entries 10–11).
Based on the above additive studies, as well as recent elegant
mechanistic investigations on (aza)-MBH reactions,13 we propose
the mechanism of 5a-catalyzed MBH reaction to be as shown
in Scheme 3. The reaction is initiated by a reversible conjugate
addition of phosphine 5a to the acrylate to generate phosphonium
enolate intermediate A, which then undergoes aldol reaction with
the aldehyde to create intermediate B. The subsequent proton
transfer, followed by b-elimination, affords the final MBH adduct
and regenerates the phosphine catalyst 5a. We propose that the
Conclusions
In summary, we have designed and prepared a series of phosphine–
thiourea organic catalysts based on the structural scaffolds of nat-
ural amino acids. In particular, L-threonine-derived bifunctional
phosphine 5a was prepared for the first time and found to be
an effective catalyst for the enantioselective MBH reaction of
acrylates with aromatic aldehydes. The desired MBH adducts were
obtained with good to very good enantioselectivities. We studied
the influences of various additives on the 5a-catalyzed MBH
reaction, and we propose that the hydrogen bonding interactions
between the thiourea and the phosphonium enolate intermediate
A are crucial for the high enantioselectivity observed. The reaction
described in this report provides a general and practical solution
to the enantioselective MBH reaction of simple acrylates, and is
anticipated to find wide applications in organic synthesis in the
future.
Experimental
General methods and materials
All the starting materials were obtained from commercial sources
and used without further purification unless otherwise stated.
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Toluene, THF and diethyl ether were dried and distilled from
sodium benzophenone ketyl prior to use. CHCl3 and CH2Cl2 were
distilled from CaH2 prior to use. Dioxane was dried and distilled
from Na prior to use. All the solvents used in reactions involving
phosphorus-containing compounds were de-gassed by N2. 1H
and 13C NMR spectra were recorded on a Bruker ACF300 or
AMX500 (500 MHz) spectrometer. Chemical shifts were reported
in parts per million (ppm), and the residual solvent peak was
used as an internal reference: proton (chloroform d 7.26), carbon
(chloroform d 77.0). Multiplicity was indicated as follows: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
(doublet of doublet), br s (broad singlet). Coupling constants
were reported in Hertz (Hz). All high resolution mass spectra
were obtained on a Finnigan/MAT 95XL-T spectrometer. For
thin layer chromatography (TLC), Merck pre-coated TLC plates
(Merck 60 F254) were used, and compounds were visualized with a
UV light at 254 nm. Further visualization was achieved by staining
with iodine, or ceric ammonium molybdate followed by heating
on a hot plate. Flash chromatographic separations were performed
on Merck 60 (0.040– 0.063 mm) mesh silica gel. The enantiomeric
excesses of products were determined by HPLC analysis on a chiral
stationary phase.
at 0 ◦C was slowly added a solution of NaPPh2 in THF/dioxane
(0.2 M in THF/dioxane, 52.0 mL, 10.40 mmol). The resulting
mixture was stirred at 0 ◦C for 2 h. The reaction was then quenched
by adding H2O (25 mL), and the mixture was extracted with ethyl
acetate (3 ¥ 30 mL). The combined organic extracts were washed
with brine (30 mL), dried over Na2SO4, filtered and concentrated.
A THF solution of HCl (4 M, 25 ml) was added to the residue,
and the resulting mixture was stirred for 1 h. The pH value of
the mixture was adjusted to 10 by slow addition of 2 M aqueous
NaOH solution at 0 ◦C. The mixture was then extracted with
ethyl acetate several times (3 ¥ 30 mL), and the combined organic
layers were washed with brine and dried over Na2SO4. Purification
by column chromatography (hexane/ethyl acetate = 5 : 1 to 1 : 1,
hexanes containing 5% Et3N) afforded 8 as a white solid (1.7 g,
78%).
1H NMR (500 MHz, CDCl3) d 7.49–7.30 (m, 10H), 3.59–3.54
(m, 1H), 2.61–2.55 (m, 1H), 2.42 (t, J = 3.5 Hz, 1H), 2.40–2.25 (m,
3H), 2.05–1.99 (m, 1H), 1.14 (d, J = 6.5 Hz, 3H); 13C NMR (125
MHz, CDCl3) d 138.8 (dd), 132.7 (dd), 129.1, 128.6 (dd), 71.0 (d),
56.7 (d), 34.6 (d), 20.0; 31P NMR (121.5 MHz, CDCl3) d -22.3
(s); HRMS (ESI) m/z calcd for C16H21NOP [M+H]+ = 274.1361,
found = 274.1362.
1-((2S,3R)-1-(Diphenylphosphino)-3-hydroxybutan-2-yl)-3-
(4-fluorophenyl)-thiourea (9). To a solution of 8 (0.81 g, 3.0
mmol) in CH2Cl2 (5 mL) under N2 was added 4-fluorophenyl
isothiocyanate (0.51 g, 3.3 mmol), and the reaction mixture
was stirred at room temperature for 2 h. The mixture was
concentrated in vacuo, and the residue was directly purified by
column chromatography (hexane/ethyl acetate = 15 : 1 to 5 : 1) to
afford 9 as a white solid (1.14 g, 90% yield).
A representative procedure for 5a-catalyzed Morita–Baylis–
Hillman (MBH) reaction
To a flame-dried round bottom flask with a magnetic stirring bar
under N2 were added methyl acrylate 11a (14 ml, 0.15 mmol),
anhydrous THF (0.4 mL), 5a (5.4 mg, 0.01 mmol) and 4 A
˚
molecular sieves (50 mg). The resulting mixture was stirred for
2 min, followed by the addition of p-nitrobenzaldehyde 10a (15.1
mg, 0.1 mmol). The flask was then sealed, and the mixture was
stirred at room temperature for 24 h. The reaction mixture was fil-
tered (to remove molecular sieves) and concentrated under reduced
pressure, and the residue was purified by column chromatography
on silica gel (hexane/EtOAc = 10 : 1 to 1 : 1) to afford 12a (21.8
mg, 92%) as a yellow solid.
1H NMR (300 MHz, CDCl3) d 8.19 (s, 1H), 7.51–7.41 (m, 4H),
7.33–7.29 (m, 6H), 7.10–6.98 (m, 4H), 6.47 (d, J = 7.7 Hz, 1H),
4.60 (br, 1H), 4.21–4.19 (m, 1H), 2.49–2.47 (m, 2H), 1.14 (d, J =
6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 180.5, 161.0 (d), 137.8
(d), 137.2 (d), 132.8 (d), 132.6 (d), 132.1, 128.8 (d), 128.6 (d), 128.5
(d), 127.1 (d), 127.1, 116.7 (d), 68.9 (d), 58.1 (d), 31.6 (d), 20.7;
31P NMR (121 MHz, CDCl3) d -23.9; HRMS (ESI) m/z calcd for
C23H25FN2OPS [M+H]+ = 427.1409, found = 427.1409.
Preparation of phosphine–thiourea catalysts 5a–5d
1-((2S,3R)-3-(tert-Butyldimethylsilyloxy)-1-(diphenylphosphi-
no)butan-2-yl)-3-(4-fluorophenyl)thiourea (5a). To the solution of
thiourea 9 (0.50 g, 1.17 mmol) in anhydrous CH2Cl2 (5 mL)
at 0 ◦C was added DIPEA (0.61 mL, 3.51 mmol), followed by
slow addition of TBSOTf (0.11 mL, 0.69 mmol). The resulting
mixture was allowed to warm to room temperature and stirring
was continued for an additional hour. The reaction was quenched
with the addition of saturated aqueous NaHCO3 (10 mL), and then
extracted with CH2Cl2 (2 ¥ 20 mL). The combined organic extracts
were washed with brine, and dried over Na2SO4. Purification by
column chromatography (hexane/ethyl acetate = 10 : 1) afforded
5a (0.58 g, 92% yield) as a white solid.
(4S,5R) - tert - Butyl - 2, 2, 5 - trimethyl - 4 - ((methylsulfonyloxy)
methyl)oxazolidine-3-carboxylate (7). To a solution of alcohol
610 (2.33 g, 9.5 mmol) in CH2Cl2 (30 mL) at 0 ◦C was added Et3N
(3.30 mL, 23.7 mmol), followed by dropwise addition of MeSO2Cl
(970 mL, 12.50 mmol) over 10 min. The reaction mixture was
stirred at room temperature for 3 h. The mixture was then washed
with water, and the aqueous layer was back extracted with CH2Cl2
several times (3 ¥ 10 mL). The combined organic extracts were
dried over Na2SO4, filtered and concentrated. Purification by silica
gel column chromatography (hexanes/ethyl acetate = 10 : 1 to 5 : 1)
afforded the desired product 7 as a colorless oil (2.64 g, 86% yield).
1H NMR (500 MHz, DMSO, 50 ◦C) d 4.43 (br, 1H), 4.34–4.31
(m, 1H), 4.15–4.12 (m, 1H), 3.62–3.59 (m, 1H), 3.17 (s, 3H), 1.54
(s, 3H), 1.44 (s, 9H), 1.41 (s, 3H), 1.2◦9 (d, J = 6.3 Hz, 3H);
1H NMR (500 MHz, CDCl3) d 7.93 (br, 1H), 7.70–7.64 (m, 2H),
7.40–7.35 (m, 5H), 7.29–7.23 (m, 3H), 7.15–7.09 (m, 2H), 7.07–
7.02 (m, 2H), 6.37 (d, J = 8.9 Hz, 1H), 4.45 (s, 1H), 4.35 (d, J =
5.7 Hz, 1H), 2.66 (dd, J = 4.4 Hz, 8.8 Hz, 1H), 2.04–2.00 (m, 1H),
13C NMR (125 MHz, DMSO, 50 C) d 150.8, 93.3, 79.5, 78.9,
72.2, 66.6, 61.2, 36.6, 27.7, 25.6, 19.1; HRMS (ESI) m/z calcd for
C13H26NO6S [M+H]+ = 324.1403, found = 324.1400.
1.09 (d, J = 6.3 Hz, 3H), 0.69 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13
C
NMR (125 MHz, CDCl3) d 180.4, 161.4 (d), 139.1, 139.0, 137.0,
136.9, 133.2(d), 132.8, 132.7, 131.9, 128.8, 128.5, 128.5, 128.4,
128.3, 127.9 (d), 117.0 (d), 68.5 (d), -4.6, 58.6 (d), 31.9 (d), 21.5,
(2R,3S)-3-Amino-4-(diphenylphosphino)butan-2-ol (8). To a
solution of 7 (2.6 g, 8.0 mmol) in anhydrous THF (20 mL) under N2
6738 | Org. Biomol. Chem., 2011, 9, 6734–6740
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17.6, -4.3, -4.6; 31P NMR (121 MHz, CDCl3) d -22.60; HRMS
(ESI) m/z calcd for C29H39FN2OPSSi [M+H]+ = 541.2274, found
= 541.2269.
Acknowledgements
We are grateful to the National University of Singapore and the
Ministry of Education (MOE) of Singapore (R-143-000-362-112)
for their generous financial support.
1-((2S,3R)-3-(((2,3-Dimethylbutan-2-yl)dimethylsilyl)oxy)-1-
(diphenylphosphino)butan-2-yl)-3-(4-fluorophenyl)thiourea
(5b).
To a solution of 9 (57.5 mg, 0.14 mmol) in THF (1 mL) at 0 ◦C was
added NaH (22.4 mg, 0.60 mmol, 60% (w/w) in mineral oil). The
mixture was stirred at 0 ◦C for 20 min, followed by the addition of
tert-butyldimethylsilyl chloride (32.5 mg, 0.18 mmol). The mixture
was then allowed to warm to room temperature and the stirring
was continued for 2 h. The reaction was quenched by the addition
of water (2 mL), and the mixture was extracted with EtOAc
several times (3 ¥ 5 mL). The combined organic extracts were
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by column chromatography (hexane/ethyl
acetate = 10 : 1 to 5 : 1) to afford 5b as a white solid (64.5 mg, 81%
yield).
1H NMR (300 MHz, CDCl3) d 7.89 (br, 1H), 7.70–7.65 (m, 2H),
7.40–7.26 (m, 8H), 7.15–7.03 (m, 4H), 6.31 (s, 1H), 4.47 (s, 1H),
4.32 (d, J = 6.0 Hz, 1H), 2.68–2.65 (m, 1H), 2.10–2.03 (m, 1H),
1.45–1.36 (m, 1H), 1.09 (d, J = 6.2 Hz, 3H), 0.69 (d, J = 6.9 Hz,
6H), 0.64 (d, J = 2.0 Hz, 6H), 0.08 (d, J = 6.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 180.5, 161.0 (d), 133.3, 133.1, 132.8, 132.6,
131.9, 128.9, 128.5, 128.6, 128.4, 128.3, 128.0 (d), 117.0 (d), 68.7
(d), 58.6 (d), 33.8, 31.7 (d), 24.6, 20.1, 18.4, 18.4, 2.4, 2.2, -2.4,
-2.4; 31P NMR (121 MHz, CDCl3) d -24.2; HRMS (ESI) m/z
calcd for C31H43FN2OPSSi [M+H]+ = 569.2587, found = 569.2589.
Notes and references
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1-((2S ,3R)-3-((tert-Butyldiphenylsilyl)oxy)-1-(diphenylphos-
phino)butan-2-yl)-3-(4-fluorophenyl)thiourea (5c). Following the
procedure described for the preparation of 5b, catalyst 5c (61%
yield) was prepared similarly. A white solid; 1H NMR (300 MHz,
CDCl3) d 7.78 (br, 1H), 7.58–7.51 (m, 4H), 7.49–7.40 (m, 4H),
7.36–7.30 (m, 7H), 7.28–7.26 (m, 5H), 7.19–7.14 (m, 2H), 7.07–
7.01 (m, 2H), 6.47 (d, J = 8.8 Hz, 1H), 4.49 (s, 1H), 4.28–4.23 (m,
1H), 2.66–2.60 (m, 1H), 2.17–2.10 (m, 1H), 0.96 (d, J = 4.5 Hz,
3H), 0.89 (s, 9H);
13C NMR (75 MHz, CDCl3) d 180.7, 161.5 (d), 137.5, 135.9,
135.8, 134.8, 133.5, 133.3, 133.0, 132.8, 132.8, 132.6, 129.9, 129.8,
129.6, 128.8, 128.5, 128.4, 128.3, 128.3, 128.1 (d), 127.7, 127.5,
117.1 (d), 70.7 (d), 58.8 (d), 32.5 (d), 29.7, 26.9, 21.4, 19.2; 31P
NMR (121 MHz, CDCl3) d -23.8; HRMS (ESI) m/z calcd for
C39H43FN2OPSSi [M+H]+ = 665.2587, found = 665.2592.
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1-((2S , 3R)-1-(Diphenylphosphino)-3((triisopropylsilyl)oxy)
butan-2-yl)-3-(4-fluorophenyl)thiourea 5d. Following the proce-
dure described for the preparation of 5b, catalyst 5d (73% yield)
was prepared similarly. A white solid; 1H NMR (300 MHz, CDCl3)
d 7.83 (br, 1H), 7.53–7.48 (m, 2H), 7.27–7.12 (m, 8H), 7.00–6.92
(m, 2H), 6.90–6.87 (m, 2H), 6.25 (d, J = 8.5 Hz, 1H), 4.34 (d,
J = 5.7 Hz, 2H), 2.58–2.51 (m, 1H), 2.06 (t, J = 10.5 Hz, 1H), 1.01
(d, J = 6.2 Hz, 3H), 0.80 (br, 21H); 13C NMR (75 MHz, CDCl3)
d 180.5, 161.5 (d), 139.0, 137.5, 137.3, 133.2, 132.9, 132.9, 132.6,
131.8, 128.7, 128.5, 128.4, 128.4, 128.3, 128.1 (d), 116.9 (d), 69.2
(d), 58.9 (d), 32.1 (d), 18.1, 18.1, 12.5; 31P NMR (121 MHz, CDCl3)
d -23.7; HRMS (ESI) m/z calcd for C32H45FN2OPSSi [M+H]+ =
583.2665, found = 583.2746.
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©