An efficient synthesis of chiral phosphinyl oxide pyrrolidines and their application to asymmetric direct aldol reactions

Article abstract of DOI:10.1039/b811581h

Chiral pyrrolidine-based phosphinyl oxides were synthesized and their performance as organocatalysts for asymmetric direct aldol reactions was evaluated. High enantioselectivities and diastereoselectivies were achieved for a range of cyclic ketones and ar

Full text of DOI:10.1039/b811581h

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An efficient synthesis of chiral phosphinyl oxide pyrrolidines and their
application to asymmetric direct aldol reactions†
Xue-Wei Liu,* Thanh Nguyen Le, Yunpeng Lu, Yongjun Xiao, Jimei Ma and Xingwei Li
Received 7th July 2008, Accepted 23rd July 2008
First published as an Advance Article on the web 4th September 2008
DOI: 10.1039/b811581h
Chiral pyrrolidine-based phosphinyl oxides were synthesized and their performance as organocatalysts
for asymmetric direct aldol reactions was evaluated. High enantioselectivities and diastereoselectivies
were achieved for a range of cyclic ketones and aromatic aldehydes.
X-ray crystallography. Chiral phosphinyl oxide pyrrolidines 4a–
Introduction
d and 5 were obtained by the removal of glucose in the presence
of acetic acid9 (Scheme 1). Compound 4a has an R configuration,
The aldol reaction is recognized as one of the most impor-
tant carbon–carbon bond-forming reactions in modern organic
and 5 has an S configuration. Homo-analogue 6 was also prepared
synthesis.1 Although highly enantioselective transition-metal cat-
alysts for asymmetric aldol reactions have been developed,2 more
attention has been directed toward developing organocatalysts
for direct aldol reactions in recent years. Since the pioneering
discovery, by List and Barbas in 2000,3 that L-proline may be
used as a catalyst in the enantioselective direct aldol reaction,
several proline derivatives, for example amides and tetrazoles,4
have been synthesized and applied in highly enantioselective direct
aldol reactions.
according to the literature method.10,11
Cyclic aminophosphonates, to the best of our knowledge, were
the first chiral pyrrolidines bearing phosphorous substituents to
catalyze the asymmetric direct aldol reaction.5 High enantioselec-
tivities were obtained and the use of organic bases as co-catalysts
favored syn-selectivity. Herein, we describe the synthesis of chiral
phosphinyl oxide pyrrolidines, with the replacement of the dihy-
droxy/diethoxy groups in pyrrolidine-based aminophosphonates
by diphenyl groups. Herein, we wish to report the preliminary
results for direct aldol reactions catalyzed by these phosphinyl
oxide compounds.
Scheme 1 Synthesis of phosphinyl oxide pyrrolidines.
The catalytic activity of 4a–d, 5 and 6 for the asymmetric direct
aldol reaction was investigated by performing a model reaction
of cyclohexanone 7 and p-nitrobenzaldehyde 8. In our initial
experiment, the reaction was performed in DMSO using catalytic
amounts (20 mol%) of phosphinyl oxide pyrrolidines. The results
are summarized in Table 1.
In most cases, the desired aldol product 9 was obtained as
a mixture of diastereomers, with the anti-(1R,2S) isomer being
predominant. Since the syn diastereomers were always the minor
products, the ee values of the anti diastereomers were primarily
considered. Compound 4a, 4c and 5 mediated the asymmetric
aldol reactions with good yield (80–90%) and good enantioselec-
tivities (79–85%) although only modest diasteroselectivities (69 :
31) were obtained (entries 1, 3 and 5). A better diastereoselectivity
(anti:syn = 80 : 20) was obtained in the reaction using 4d as
catalyst (entry 4). In contrast, compound 4b and 6 catalyzed
the formation of nearly 1 : 1 mixture of anti:syn products with
moderate enantioselectivity (entry 2 and 6).
Results and discussion
The chiral pyrrolidine derivatives 4a–d bearing phosphinyl sub-
stituents were synthesized from pyrrolidine. Reaction of pyrroli-
dine with sodium peroxodisulfate and sodium hydroxide in the
presence of silver nitrate catalyst afforded triazine compound 1
in 48% yield.6 The triazine was then reacted with different
phosphine oxides to give racemic mixtures 2a–d of phosphinyl-
pyrrolidines.7 We were able to separate the two enantiomers
by glycosylation.8 Treatment of the racemic mixture with D-
glucose in methanol led to the formation of two diastereomeric
N-glucosylation products that could be separated by column
chromatography; their absolute configuration was assigned by
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University, 637371,
Singapore. E-mail: xuewei@ntu.edu.sg; Fax: +65 6316 6984; Tel: +65 6316
8901
† Electronic supplementary information (ESI) available: Spectral and
crystallographic data. CCDC reference numbers [CCDC NUMBER(S)].
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b811581h
Compound 4a was chosen for further studies on the basis of
good enantioselectivity and ease of preparation on a large scale.
The solvents, catalyst loading, temperature and the additives in
the reaction were extensively studied for this catalyst. Results
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Table 1 Screening of catalysts for the model asymmetric aldol reaction of p-nitrobenzaldehyde with cyclohexanone
Entry
Catalyst
Time/h
Yield (%)a
dr (anti:syn)b
% ee (anti)b
1
2
3
4
5
6
4a
4b
4c
4d
5
120
102
96
124
120
96
90
33
86
79
79
55
69 : 31
52 : 48
67 : 33
80 : 20
69 : 31
55 : 45
85
63
79
84
81
35
6
a Isolated yield after silica gel chromatography. b Determined by chiral HPLC; the anti-isomer is the major product.
show that the reaction in DMSO afforded the anti product with
the highest yield and enantioselectivity; reactions in DCM and
chloroform gave slightly better anti:syn ratios but with lower
yields and enantioselectivities (Table 2, entries 1–5). Furthermore,
reduction in catalyst loading to 5–10% resulted in sluggish
reactions with poor yields (entry 6 and 7). Therefore, 20 mol%
was the preferred catalyst loading.
The effect of additives on the asymmetric aldol reactions was
examined. The addition of acids and bases has been reported to
accelerate the reaction rate by promoting enamine formation.5,12
Unsatisfactory results were observed with the addition of strong
acid of HCOOH and TsOH (entries 10 and 11), but the reaction
rate was enhanced and good enantioselectivities were observed
when weaker acids, AcOH and PhCOOH, were used as the
additives (entries 8 and 9).
significantly (entries 12–14). Based on our extensive screening
results, we concluded that the optimal reaction conditions were
to utilize 4a as a catalyst, AcOH as an additive, and DMSO as
solvent at room temperature.
Under our optimized reaction conditions, the application of
catalyst 4a in the direct asymmetric intermolecular aldol reaction
between different aromatic aldehyde acceptors and ketone donors
was further explored (Table 3). The best enantioselectivity of
93% was obtained in the reaction between thiopyranone and
p-nitrobenzaldehyde with an anti:syn ratio of 85 : 15 (entry 2).
Aldol reactions of 3,4-dihydro-2H-thiopyranone with m-nitro-
benzaldehyde or o-nitrobenzaldehyde gave a slightly lower anti:syn
ratio of 83 : 17 and an ee of 82–87% (entries 6 and 8). The highest
anti:syn ratio of 86 : 14 was observed between the reaction of
p-nitrobenzaldehyde and 3,4-dihydro-2H-pyranone (entry 3). 4-
Methylcyclohexanone and N-Boc-piperidin-4-one were also em-
ployed in the aldol reactions but showed lower enantioselectivities
compared to cyclohexanone in our catalytic system (entries 4
To further improve the diastereoselectivity, we investigated the
effect of temperature on the reaction. To our disappointment, the
reaction proceeded very slowly at 0 ◦C. At 50 ◦C, the ee dropped
Table 2 Enantioselective direct aldol reaction of p-nitrobenzaldehyde with cyclohexanone catalyzed by 4a under various conditions
Entry
Additive
Solvent
Time/h
Yield (%)a
dr (anti:syn)b
% ee (anti)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
—
—
—
—
—
—
—
AcOH
PhCO2H
HCO2H
TsOH
AcOH
AcOH
PhOH
DCM
CHCl3
DMF
96
96
96
96
96
192
144
48
48
48
48
48
29
29
77
88
48
56
90
55
61
73
58
64
Trace
Trace
73
77 : 23
74 : 26
66 : 24
57 : 43
69 : 31
68 : 32
74 : 26
69 : 31
70 : 30
64 : 26
—
72
60
71
70
85
82
83
85
80
74
—
—
60
64
THF
DMSO
DMSOc
DMSOd
DMSO
DMSO
DMSO
DMSO
DMSOe
DMSOf
DMSOf
—
62 : 38
69 : 31
78
a Isolated yield after silica gel chromatography. b Determined by chiral HPLC; the anti-isomer is the major product. c Only 5% catalyst was used. d Only
10% catalyst was used. e Reaction carried out at 0 ◦C. f Reaction carried out at 50 ◦C.
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Table 3 The direct aldol reaction catalyzed by catalyst 4a with different aldehydes and ketones
Entry
R
X
Time/h
Yield (%)a
dr (anti:syn)b
% ee (anti)b
1
2
3
4
5
6
7
8
9
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
m-NO2
m-NO2
o-NO2
o-NO2
CH2
S
O
CHMe
NBoc
S
O
S
O
48
41
60
48
60
48
48
48
48
73 (9)
69 : 31
85 : 15
86 : 14
64 : 26
69 : 31
83 : 17
74 : 26
83 : 17
83 : 17
85
93
82
85
80
87
82
82
89
44 (12a)
60 (12b)
61 (12c)
43 (12d)
76 (12e)
73 (12f)
66 (12g)
75 (12h)
a Isolated yield after silica gel chromatography. b Determined by chiral HPLC; the anti-isomer is the major product.
Table 4 The reaction barrier (Ea‡) and free energy (DG◦‡) of activation
and 5). The current method has its limitations since we can not
extend it to simple acyclic ketones and non-aromatic aldehydes.
Theoretical calculations have been performed to understand
the mechanism of our catalytic system. It is well known that the
key step in amine-catalyzed aldol reactions is the formation of
the carbon–carbon single bond in the reaction of the enamine
intermediate and aldehyde or acetone.13 Unlike proline-catalyzed
aldol reactions, there is no H-bonding involved in the transition
state for carbon–carbon bond formation. Fig. 1a shows one of
many possible transition state geometries without an acid additive
in the gas phase. p-Nitrobenzaldehyde approaches the enamine
intermediate preferentially from the side opposite to the bulky
phosphine oxide group. The transition state has a C–C bond length
at room temperature for reaction without acid additive
Gas phase
CHCl3
DCM
DMSO
THF
Ea (kcal mol-1)
32.82
44.74
29.81
45.31
29.30
46.69
29.12
44.05
29.62
43.30
‡
DG◦ (kcal mol-1)
‡
have predicted that for such reactions, there is almost no reaction
barrier.13 In our calculation, the reaction barrier is about 4.33 kcal
mol-1 after zero-point energy correction, which is in agreement
with their calculations. However, at room temperature, the free
energy of activation is about 28.05 kcal mol-1, due to the entropy
penalty.
˚
˚
=
of 1.6847 A and a C N bond length of 1.3182 A. This zwitterionic
structure leads to an oxetane intermediate. The reaction barrier is
32.82 kcal mol-1 after zero-point energy correction at B3LYP/6-
31G(d) calculation, and the free energy of activation is 44.74 kcal
mol-1, a relatively high value.
◦
‡
‡
The reaction barrier (Ea ) and free energy of activation (DG )
at room temperature for the gas phase and for different solvents
are reported in Table 4 for reactions without acid additive. The
results show that different solvents do not change the reaction
barrier and free energy of activation very much and the reactions
are slow, in agreement with observation. With AcOH as the acid
additive, the reaction barrier is 8.72 kcal mol-1 and the free energy
of activation at room temperature is about 35.71 kcal mol-1 in
DMSO solution, so whether in gas phase or in solution, the acid
additive can promote the direct aldol reactions.
In summary, we have demonstrated the direct aldol reaction
of cyclic ketones with different aromatic aldehydes catalyzed by
phosphinyl oxide pyrrolidines with good yields, moderate diastere-
oselectivities, and up to 93% ee. The catalytic transition state was
rationalized by the DFT calculations. Further exploration of this
catalyst in other asymmetric reactions is under way.
Fig. 1 The calculated transition state of aldol reaction of 7 and 8 catalyzed
by 4a. a) without acid additive, left; b) with acetic acid additive, right.
Experimental
Fig. 1b shows a possible transition state geometry with AcOH
as acid additive in the gas phase. The forming C–C bond length is
General
˚
˚
=
1.6529 A and C N bond length is 1.3073 A. In this transition state,
the hydrogen ion from acetic acid has been partially transferred to
the oxygen atom of the carboxyl group in p-nitrobenzaldehyde, as
Unless otherwise noted, all reactions were carried out in oven-
dried glassware under an atmosphere of nitrogen, and distilled
solvents were transferred by syringe. Solvents and reagents were
purified according to standard procedures prior to use. Product
purification by flash column chromatography was accomplished
using silica gel 60 (0.010–0.063 nm). NMR spectra were recorded
˚
˚
the calculated two O–H bond lengths are 1.1634 A and 1.2596 A
and the O–H–O angle is 172.4◦. The bond length of C–O in p-
˚
nitrobenzaldehyde is elongated to 1.3515 A. Bahmanyar and Houk
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at room temperature on a 300 MHz Bruker ACF 300 or a 400 MHz
Bruker DPX 400 instrument. The residual solvent signals were
taken as the reference (7.26 ppm for H NMR spectra and 77.0
CDCl3) d: 154.9, 154.8, 131.4, 130.8, 129.6, 128.6, 127.6, 125.4,
56.8, 48.1, 34.7, 30.9, 26.4, 26.2. 31P NMR (CDCl3) d: 31.3.
HRMS, calc. for C24H34NOP: 383.2378, found: 383.2364.
1
ppm for 13C NMR spectra). Chemical shifts (d) are reported in
ppm, and coupling constants (J) are given in Hz. The following
abbreviations classify the multiplicity: s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet or unresolved, br =
broad signal. Infrared spectra were recorded on a Bio-RAD FTS
165 FT-IR spectrometer and are reported in cm-1. Samples were
prepared using the thin film technique. HR-MS (ESI) spectra
were recorded on a Finnigan/MAT LCQ quadrupole ion trap
mass spectrometer, coupled with the TSP4000 HPLC system
and the Crystal 310 CE system. X-Ray crystallographic data
was collected by using a Bruker X8 Apex diffractometer with
MoKa radiation (graphite monochromator). The ee values were
determined by HPLC using a Daicel AD-H, or OD-H column,
l = 254 nm.
General procedure for compounds 3a–d
The racemic 2-diphenylphosphinylpyrrolidine 2a–d (14 mmol),
a-D-glucose (42 mmol) and (NH4)2SO4 (55 mg, 0.42 mmol)
were refluxed in MeOH (40 mL) for 26 h. The solvent was
removed under vacuum and the residue was purified by silica gel
chromatography (DCM–MeOH, 8 : 1) to obtain the intermediate
3a–3d.
(2R,3S,4R,5S)-2-((R)-2-(Diphenylphosphoryl)pyrrolidin-1-yl)-
6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,
3a. Yield
47%. [a]2D5 = -11.83 (c = 1.0, CH2Cl2). IR (Nujol, cm-1): 3446
1
=
(OH), 1589, 1487, 1440 (phenyl), 1215 (P O). H NMR (400 MHz,
CDCl3) d: 7.99–7.96 (m, 2H), 7.89–7.86 (m, 2H), 7.61–7.52 (m,
6H), 4.53–4.47 (m, 1H), 3.86–3.83 (m, 1H), 3.58–3.54 (m, 1H),
3.39–3.30 (m, 3H), 3.24 (t, J = 8.9, 1H), 3.12–3.04 (m, 2H),
2.99-2.97 (m, 1H), 2.88-2.82 (m, 2H), 2.22-2.13 (m, 1H), 2.00-1.95
(m, 1H), 1.76-1.71 (m, 1H), 1.65-1.59 (m, 1H). 13C NMR (100
MHz, CDCl3) d: 132.04, 131.7, 131.5, 131.0, 130.6, 129.2, 128.5,
128.4, 91.3, 78.0, 77.6, 71.8, 70.5, 61.9, 58.1, 45.4, 27.2, 24.7.
31P NMR (CDCl3) d: 31.7. HRMS, calculated for C22H28NO6P:
433.1654, found: 433.1716.
General procedure for racemic compounds 2a–d
A solution of triazine 16 (2.07 g, 10 mmol) and diphenylphosphine
oxide (6.06 g, 30 mmol) in toluene (100 ml) was refluxed for 3 h.
Toluene was removed under vacuum and the residue was purified
by silica gel chromatography (DCM–MeOH, 40 : 1) to obtain the
racemic 2-diphenylphosphinylpyrrolidine 2.
Crystal data for 3a·2H2O. C22H32NO8P, M = 469.46, prism, a =
2-(Diphenylphosphoryl)pyrrolidine, 2a. Yield 88%. IR (Nujol,
◦
◦
˚
˚
˚
-1
cm ): 3419 (NH), 1618, 1456, 1436 (phenyl), 1180 (P O). 1H
8.0227(3) A, b = 8.8488(4) A, c = 31.8469(13) A, a = 90 , b = 90 ,
=
◦
3
˚
g = 90 , V = 2260.85(16) A , space group P212121, T = 173(2) K,
NMR (300 MHz, CDCl3) d: 7.77–7.90 (m, 4H), 7.43–7.53 (m,
6H), 3.88–3.93 (m, 1H), 2.98–3.03 (m, 1H), 2.88–2.94 (m, 1H),
1.92–2.0 (m, 3H), 1.71–1.78 (m, 2H). 13C NMR (75 MHz, CDCl3)
d: 131.8, 131.7, 131.5, 130.9, 128.4, 56.9, 48.3, 26.5, 26.4. 31 P NMR
(CDCl3) d: 32.0. HRMS, calc. for C16H18NOP: 271.1126, found:
271.1121.
Z = 4, F(000) = 1000, Dcalc = 1.739 Mg m-3, 6889 total reflections
collected, 2937 Friedel pairs used. X-Ray crystallographic data
was collected by using a Bruker X8 Apex diffractometer with
graphite-monochromated MoKa radiation.
(2R,3S,4R,5S)-2-((R)-2-(Bis(3-(trifluoromethyl)phenyl)phos-
phoryl)pyrrolidin-1-yl)-6-(hydroxylmethyl)tetrahydro-2H-pyran-
3,4,5-triol, 3b. Yield 33%. [a]2D5 = -12.36 (c = 1.0, CH2Cl2). IR
2-(Bis(3-(trifluoromethyl)phenyl)phosphoryl)pyrrolidine,
2b.
Yield 83%. IR (Nujol, cm-1): 3296.4 (NH), 1604.8, 1479.4, 1421.5
-1
1
=
(Nujol, cm ): 3369 (OH), 1604, 1421 (phenyl), 1215 (P O). H
NMR (400 MHz, CDCl3) d: 8.39-8.31 (m, 2H), 8.27-8.21 (m,
2H), 7.92 (d, J = 7.78, 2H ), 7.80–7.75 (m, 2H), 4.69–4.60 (m,
1H), 3.90–3.86 (m, 1H), 3.61–3.55 (m, 1H), 3.41 (d, J = 8.99,
1H), 3.34–3.28 (m, 3H), 3.17–3.07 (m, 2H), 3.00-2.87 (m, 3H),
2.27–2.16 (m, 1H), 1.98–1.95 (m, 1H), 1.78–1.75 (m, 1H), 1.61–
1.58 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 135.3, 134.7,
133.6, 132.3, 131.2, 130.9, 129.6, 128.8, 128.6, 127.7, 125.5, 122.9,
92.0, 78.0, 77.7, 71.7, 70.4, 61.8, 58.4, 45.4, 27.0, 24.0. 31P NMR
(CDCl3) d: 30.9. HRMS, calc. for C30H44NO6P: 545.2906, found:
545.2916.
1
=
(phenyl), 1168.9 (P O). H NMR (400 MHz, CDCl3) d: 8.30 (d,
J = 10.6, 1H), 8.20–8.17 (m, 2H), 8.03–7.98 (m, 1H), 7.77–7.73
(m, 2H), 7.59-7.56 (m, 2H), 3.97–3.92 (m, 1H), 2.97-2.91 (m,
1H), 2.82-2.79 (m, 1H), 2.11-2.04 (m, 1H), 1.94–1.835 (m, 2H),
1.66–1.64 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 135.1, 134.2,
133.2, 132.3, 131.4, 131.0, 129.1, 128.9, 128.5, 127.9, 124.8, 122.1,
56.7, 48.0, 26.5, 26.4. 31P NMR (CDCl3) d: 28.21. HRMS, calc.
for C18H16F6NOP: 407.0874, found: 407.0826.
2-(Di-p-tolylphosphoryl)pyrrolidine, 2c. Yield 79%. IR (Nujol,
-1
1
=
cm ): 3280 (NH), 1600, 1452 (phenyl), 1168 (P O). H NMR (400
MHz, CDCl3) d: 7.76–7.71 (m, 2H), 7.63–7.58 (m, 2H), 7.18–7.16
(m, 4H), 3.77–3.74 (m, 1H), 2.92-2.89 (m, 1H), 2.82-2.79 (m, 1H),
2.42 (brs, 1H), 2.28 (s, 3H), 1.90–1.83 (m, 2H), 1.67–1.62 (m, 2H).
13C NMR (100 MHz, CDCl3) d: 141.8, 131.5, 130.8, 129.6, 129.0,
128.8, 128.5, 127.5, 56.7, 48.0, 26.3, 26.1, 21.2. 31P NMR (CDCl3)
d: 31.7. HRMS, calc. for C18H22NOP: 299.1439, found: 299.1433.
(2R,3S,4R,5S)-2-((R)-2-(Di-p-tolylphosphoryl)pyrrolidin-1-yl)-
6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,
3c. Yield
46%. [a]2D5 = -16.08 (c = 1.0, CH2Cl2). IR (Nujol, cm-1): 3412
1
=
(OH), 1600, 1437, 1419 (phenyl), 1222 (P O). H NMR (400 MHz,
CDCl3) d: 7.85–7.81 (m, 2H), 7.75–7.70 (m, 2H), 7.36–7.30 (m,
4H), 4.45–4.41 (m, 1H), 3.86–3.83 (m, 1H), 3.59–3.54 (m, 1H),
3.43–3.41 (m, 1H), 3.34–3.30 (m, 2H), 3.23 (t, J = 8.9, 1H),
3.11–3.04 (m, 2H), 2.98–2.95 (m, 1H), 2.90–2.83 (m, 2H), 2.39
(s, 6H), 2.17–2.09 (m, 1H), 1.99–1.93 (m, 1H), 1.73–1.70 (m,
1H), 1.63–1.58 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 142.7,
131.6, 130.9, 129.0, 128.7, 127.6, 127.4, 126.4, 91.2, 77.9, 77.6,
71.7, 70.4, 61.8, 58.0, 45.3, 27.1, 24.6, 20.1, 20.1. 31P NMR
2-(Bis(4-tert-butylphenyl)phosphoryl)pyrrolidine,
2d. Yield
89%. IR (Nujol, cm-1): 3421 (NH), 1599, 1460 (phenyl), 1176
(P O). 1H NMR (400 MHz, CDCl3) d: 7.84–7.79 (m, 2H),
=
7.71–7.67 (m, 2H), 7.44–7.41 (m, 4H), 3.84–3.80 (m, 1H), 3.13
(brs, 1H), 3.00-2.98 (m, 1H), 2.87-2.85 (m, 1H), 1.97–1.95 (m,
2H), 1.67–1.62 (m, 2H), 1.26(s, 18H). 13C NMR (100 MHz,
4000 | Org. Biomol. Chem., 2008, 6, 3997–4003
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(CDCl3) d: 33.7. HRMS, calc. for C24H32NO6P: 461.1967, found:
General procedure for the aldol reaction
461.1920.
A mixture of phosphorylpyrrolidine catalyst (0.1 mmol), ketone
(2.5 mmol) and the additive (0.1 mmol) were stirred in 1 mL
DMSO for 15 min at rt. The aldehyde (0.5 mmol) was added and
the mixture was stirred for several hours. The mixture was treated
with 1 mL of saturated ammonium chloride solution and extracted
with ethyl acetate. The organic layer was dried (MgSO4), filtered
and concentrated to give crude aldol adduct. The anti-isomer was
purified by flash column chromatography on silica gel (hexane–
ethyl acetate, 4 : 1).
(2R,3S,4R,5S)-2-((R)-2-(Bis(4-tert-butylphenyl)phosphoryl)-
pyrrolidin-1-yl)-6-(hydroxymethyl)tetrahydro-2H -pyran-3,4,5-
triol, 3d. Yield 42%. [a]D25 = -11.57 (c = 1.0, CH2Cl2). IR (Nujol,
-1
1
=
cm ): 3402 (OH), 1599, 1458, 1442 (phenyl), 1215 (P O). H NMR
(400 MHz, CDCl3) d: 7.90–7.85 (m, 2H), 7.79–7.76 (m, 2H), 7.59–
7.57 (m, 4H), 4.46–4.40 (m, 1H), 3.86–3.82 (m, 1H), 3.58–3.54 (m,
1H), 3.43–3.41 (m, 1H), 3.34–3.30 (m, 2H), 3.22 (t, J = 8.9, 1H),
3.13–3.04 (m, 2H), 2.99–2.95 (m, 1H), 2.88–2.77 (m, 2H), 2.19–
2.11 (m, 1H), 2.02–1.93 (m, 1H), 1.75–1.71 (m, 1H), 1.64–1.58
(m, 1H), 1.33 (d, J = 3.7, 18H). 13C NMR (100 MHz, CDCl3) d:
155.7, 132.4, 131.5, 127.5, 126.3, 126.1, 125.6, 125.1, 91.1, 77.8,
77.7, 71.7, 70.4, 61.8, 58.0, 45.3, 34.4, 30.0, 27.1, 24.6. 31P NMR
(CDCl3) d: 33.7. HRMS, calc. for C30H44NO6P: 545.2906, found:
545.2916.
(S)-2-((R)-Hydroxy-(4-nitrophenyl)methyl)cyclohexanone,
9-
1
anti. Yield 73%. H NMR (400 MHz, CDCl3) d: 8.20 (d, J =
8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.89 (dd, J = 8.3 Hz, 2.8 Hz,
1H), 4.08 (d, J = 3.0 Hz, 1H), 2.62–2.55 (m, 1H), 2.50–2.47 (m,
1H), 2.38–2.31 (m, 1H), 2.13–2.08 (m, 1H), 1.65–1.53 (m, 3H),
1.41–1.35 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 214.7, 148.3,
147.5, 127.8, 123.5, 73.9, 57.1, 42.6, 30.7, 27.6, 24.6. HPLC:
Chiralpak AD-H column, hexane–i-PrOH 90 : 10, flow rate 1 mL
min-1; tR (anti-minor) = 22.5 min; tR (anti-major) = 29.8 min.
Synthesis of the enantiopure 2-diphenylphosphinylpyrrolidines
4a–d and 5
(S)-3-((R)-Hydroxy-(4-nitrophenyl)methyl)dihydro-2H-thiopy-
ran4(3H)-one, 12a-anti. Yield 44%. 1H NMR (400 MHz, CDCl3)
d: 8.22 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 5.05 (dd, J =
8.0, 3.6 Hz, 1H), 3.66 (br s, 1H), 3.02–2.96 (m, 3H), 2.85–2.76 (m,
2H), 2.79–2.63 (m, 1H), 2.54–2.49 (m, 1H). 13C NMR (100 MHz,
CDCl3) d: 211.2, 147.7, 147.6, 127.7, 123.8, 73.1, 59.4, 44.7, 32.8,
30.8. HPLC: Chiralpak AD-H column, hexane–i-PrOH 90 : 10,
flow rate 1 mL min-1; tR (anti-minor) = 47.1 min; tR (anti-major) =
56.5 min.
A mixture of the intermediate 3a–d (0.5 g, 1.15 mmol), acetone
(5 mL), water (1 mL), and acetic acid (0.2 mL) was heated under
reflux for 2 h and then concentrated. The residue was purified
by silica gel chromatography (DCM–MeOH, 8 : 1) to obtain the
enantiopure 2-diphenylphosphinylpyrrolidine 4a–d and 5.
(R)-2-(Diphenylphosphoryl)pyrrolidine, 4a. Yield 49%. [a]D25
-9.6 (c = 1.0, CH2Cl2). Retention time: 22.60 min (HPLC chiral
=
AD-H column, hexane–i-PrOH = 90 : 10, 1 mL min-1).
(S)-3-((R)-Hydroxy-(4-nitrophenyl)methyl)dihydro-2H-pyran-
4(3H)-one, 12b-anti. Yield 60%. 1H NMR (400 MHz, CDCl3) d:
8.21 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 4.96 (dd, J =
8.1, 3.3 Hz, 1H), 4.23–4.18 (m, 1H), 3.83–3.70 (m, 3H), 3.46 (t, J =
9.9 Hz, 1H), 2.90–2.88 (m, 1H), 2.69–2.66 (m, 1H), 2.54–2.50 (m,
1H). HPLC: Chiralpak AD-H column, hexane–i-PrOH 90 : 10,
flow rate 1 mL min-1; tR (anti-minor) = 37.2 min; tR (anti-major) =
45.0 min.
(R)-2-(Bis(3-(trifluoromethyl)phenyl)phosphoryl)pyrrolidine 4b.
Yield 39%. [a]2D5 = -5.2 (c = 1.0, CH2Cl2).
(R)-2-(Di-p-tolylphosphoryl)pyrrolidine, 4c. Yield 60%. [a]D25
-6.7 (c = 1.0, CH2Cl2).
=
(R)-2-(Bis(4-tert-butylphenyl)phosphoryl)pyrrolidine, 4d. Yield
42%. [a]2D5 = -3.4 (c = 1.0, CH2Cl2).
(2S)-2-((R)-Hydroxy-(4-nitrophenyl)methyl)-4-methylcyclohex-
anone, 12c-anti. Yield 61%. 1H NMR (400 MHz, CDCl3) d: 8.21
(d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 4.91 (d, J = 8.4
Hz, 1H), 3.91 (d, J = 2.4 Hz, 1H), 2.77–2.71 (m, 1H), 2.57–2.49
(m, 1H), 2.42–2.35 (m, 1H), 2.10–2.06 (m, 1H), 1.97–1.89 (m, 1H),
1.82–1.76 (m, 1H), 1.63–1.55 (m, 1H), 1.34–1.27 (m, 1H), 1.05 (d,
J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) d: 214.9, 148.3,
147.6, 127.7, 123.6, 74.1, 52.8, 38.1, 36.0, 32.8, 26.5, 18.1. HPLC:
Chiralpak OD-H column, hexane–i-PrOH 95 : 5, flow rate 1 mL
min-1; tR (anti-major) = 70.6 min; tR (anti-minor) = 86.3 min.
(S)-tert-Butyl-3-((R)-hydroxy-(4-nitrophenyl)methyl)-4-oxopi-
peridine-1-carboxylate, 12d-anti. Yield 43%. 1H NMR (400
MHz, CDCl3) d: 8.24 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 8.9 Hz,
2H), 4.99 (dd, J = 8.0, 2.7 Hz, 1H), 4.17–4.11 (m, 1H), 3.88 (d,
J = 3.6 Hz, 1H), 3.88–3.70 (m, 1H), 3.27 (br, 1H), 2.93 (t, J = 11.3
Hz, 1H), 2.76 (br, 1H), 2.59–2.48 (m, 2H), 1.40 (s, 9H). 13C NMR
(100 MHz, CDCl3) d: 210.0, 154.2, 147.6, 147.1, 127.7, 123.6,
81.0, 71.7, 56.4, 43.7, 42.8, 41.5, 28.3. HPLC: HPLC: Chiralpak
OD-H column, hexane–i-PrOH 97 : 3, flow rate 1 mL min-1; tR
(anti-major) = 63.0 min; tR (anti-minor) = 71.9 min.
(S)-2-(Diphenylphosphoryl)pyrrolidine, 5. Yield 45%. [a]D25
=
+9.7 (c = 1.0, CH2Cl2). Retention time: 15.32 min (HPLC chiral
AD-H column, hexane–i-PrOH 90 : 10, 1 mL min-1).
(S)-2-((Diphenylphosphoryl)methyl)pyrrolidine 6
To a solution of (S)-2-((diphenylphosphino)methyl)pyrrolidine10
(500 mg, 1.85 mmol) in chloroform (20 mL) was added slowly
at room temperature 25 mL of a 10% aqueous solution of H2O2.
After being stirred for 2 h and hydrolytic workup, the residue
was purified by silica gel chromatography (DCM–MeOH, 40 : 1)
to obtain compound 6 as a white solid (474 mg, 90%). IR (Nujol,
-1
1
=
cm ): 3419 (NH), 1618, 1456, 1436 (phenyl), 1180 (P O). H NMR
(300 MHz, CDCl3) d: 7.75–7.69 (m, 4H), 7.45–7.25 (m, 6H), 3.39–
3.34 (m, 1H), 3.00–2.96 (m, 1H), 2.82–2.75 (m, 1H), 2.61–2.41 (m,
2H), 1.93–1.62 (m, 3H), 1.42–1.37(m, 1H). 13C NMR (75 MHz,
CDCl3) d: 133.1, 133.0, 131.7, 130.8, 130.7, 130.6, 128.7, 128.6,
53.2, 45.5, 35.8, 33.0, 24.2. 31P NMR (CDCl3) d: 30.8. HRMS,
calc. for C16H18NOP: 285.1283, found: 285.1221.
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(S)-3-((R)-Hydroxy(3-nitrophenyl)methyl)dihydro-2H -thio-
pyran-4(3H)-one, 12e-anti. Yield 76%. 1H NMR (400 MHz,
CDCl3) d: 8.24-8.16 (m, 2H), 7.70 (d, J = 7.7 Hz, 1H), 7.55 (d,
J = 7.9 Hz, 1H), 5.04 (dd, J = 8.2, 4.0 Hz, 1H), 3.69 (d, J = 4.0
Hz, 1H), 3.07–2.95 (m, 3H), 2.85–2.76 (m, 2H), 2.68 (dd, J = 13.7,
11.0 Hz, 1H), 2.52 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 211.4,
148.4, 142.6, 133.0, 129.6, 123.2, 122.0, 73.2, 59.4, 44.8, 32.8, 30.8.
HPLC: Chiralpak AD-H column, hexane–i-PrOH 90 : 10, flow
rate 1 mL min-1; tR (anti-major) = 63.2 min; tR (anti-minor) =
89.1 min.
Acknowledgements
This work was supported by Nanyang Technological University
and the Ministry of Education, Singapore. We also thank Dr
Roderick W. Bates and Dr Guan-Leong Chua for discussion and
help in the preparation of this manuscript.
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rate 1 mL min-1; tR (anti-minor) = 24.3 min; tR (anti-major) =
30.1 min.
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(3H)-one, 12h-anti. Yield 75%. 1H NMR (400 MHz, CDCl3) d:
7.90 (dd, J = 8.4, 1.2 Hz, 1H), 7.80 (dd, J = 8.4, 1.2 Hz, 1H)
7.68–7.63 (m, 1H), 7.48–7.42 (m, 1H), 5.46 (d, J = 6.6 Hz, 1H),
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Computational details
DFT calculations were carried out with the Gaussian 03 package.14
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structures obtained were confirmed to be a true minimum or
saddle point by harmonic frequency calculations at the same level
of theory. Transition states were further confirmed by intrinsic
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(Revision D.01), Gaussian, Inc., Wallingford, CT, 2004.
4002 | Org. Biomol. Chem., 2008, 6, 3997–4003
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This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3997–4003 | 4003
©