Highly enantioselective Pd-catalyzed asymmetric hydrogenation of N-diphenylphosphinyl ketimines

Article abstract of DOI:10.1055/s-2006-939712

A variety of substituted N-diphenylphosphinyl imines were hydrogenated using Pd(CF₃CO₂)₂/(S)-SEGPHOS as a catalyst with high enantioselectivities (86.7%-98.6% ee). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939712

LETTER
1189
Highly Enantioselective Pd-Catalyzed Asymmetric Hydrogenation of
N-Diphenylphosphinyl Ketimines
Enantioselective
P
o
d-Catalyzed
u
A
symmetric
-
H
ydroge
Q
nation of
N
-Diphe
i
nylpho
n
sphinyl
K
eti
g
mines Wang, Yong-Gui Zhou*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, P. R. of China
Fax +86(411)84379220; E-mail: ygzhou@dicp.ac.cn
Received 16 November 2005
N-diphenylphosphinyl imines 1 using Pd catalysts with up
to 98.6% ee. N-Diphenylphosphinyl imines 1 can be con-
veniently prepared from the corresponding oximes.9
Asymmetric hydrogenation of 110 is one of the simple and
efficient ways to synthesize chiral amines 2,9a,11,12 which
can be readily converted to free amines under mild condi-
tions (Scheme 1).
Abstract: A variety of substituted N-diphenylphosphinyl imines
were hydrogenated using Pd(CF3CO2)2/(S)-SEGPHOS as a catalyst
with high enantioselectivities (86.7%–98.6% ee).
Key words: palladium, asymmetric synthesis, hydrogenation, N-
diphenylphosphinyl imines
Transition-metal-catalyzed asymmetric synthesis is a
powerful and commonly used method for preparing a
wide range of enantiomerically pure compounds.1 Among
organo-transition-metal compounds, Pd complexes have
become indispensable tools for both common and state-
of-the art organic synthesis.2 Although a large number of
Pd-based catalytic systems have been developed for many
kinds of reactions, Pd chemistry has still not achieved its
full potential. So, the search for improved Pd-catalyzed
reactions continues with the goal of increasing the diver-
sity of possible substrates and reaction types.
P(O)Ph2
R
P(O)Ph2
R
Chiral catalyst
H2
N
HN
Ar
Ar
1
2
Scheme 1
On the basis of previous work on the Pd-catalyzed asym-
metric hydrogenation of ketones8 and imines,6 initial stud-
ies on the influence of the reaction conditions were carried
out with 1a as a standard substrate (Table 1). The hydro-
genation reaction was conducted in 2,2,2-trifluoroethanol
(TFE) at 600 psi of hydrogen using Pd(OCOCF3)2/(R)-
SYNPHOS as the catalyst. We were pleased to find an ee
of 94.6%, albeit, with 85% conversion (Table 1, entry 1).
Asymmetric hydrogenation utilizing molecular hydrogen
to reduce prochiral alkenes, ketones, and imines, is one of
the most powerful methods in asymmetric catalysis.1,3 In
contrast to the enantioselective hydrogenation of both al-
kenes and ketones, only limited success has been achieved
in the enantioselective hydrogenation of imines.4 The
majority of catalysts for the asymmetric hydrogenation of
imines are chiral Ir, Rh, and Ru complexes.4 There are
only a few reports on the asymmetric hydrogenation of
imines using Pd complexes, although many successful ex-
amples of heterogeneous asymmetric hydrogenation reac-
tions catalyzed by Pd(0) have been well documented in
the literature.5 In 2001, Amii et al. first reported the asym-
metric hydrogenation of a-fluorinated iminoesters with a
Pd(CF3CO2)2/BINAP complex.6 Alper et al. reported the
Pd-catalyzed asymmetric double carbohydroamination of
iodobenzene for the synthesis of chiral a-aminoamides
with high enantioselectivity. The reaction was suggested
to involve a Pd-catalyzed asymmetric hydrogenation of
a-iminoamide intermediates; however, no evidence to
support this claim was proffered.7
We then turned our attention to examine the effect of sol-
vent, reaction temperature, Pd precursor, and hydrogen
pressure on reactivity and enantioselectivity (Table 1). A
strongly solvent-dependent phenomenon was observed
(Table 1, entries 1–7); TFE is the most effective solvent,
which was also the case in the Pd-catalyzed asymmetric
hydrogenation of imines6 and functionalized ketones.8 A
change in reaction temperature had no clear effect on
conversion (Table 1, entry 1 vs 8), but the ee slightly de-
creased at a higher temperature (Table 1, entry 8). Other
Pd precursors were also tested in the reaction (Table 1, en-
tries 1, 9–11). Neutral PdCl2 gave lower catalytic activity,
while Pd precursors with weakly coordinating anions such
–
–
as CF3CO2 and CH3CO2 provided similar results. Sur-
prisingly, Pd(OTf)2 gave worse results, which is in con-
trast to the asymmetric hydrogenation of a-phthalimide
ketones8 where the same result was achieved with
Pd(OCOCF3)2. To our delight, an increase in the hydrogen
pressure led to full conversion with the same enantioselec-
tivity (Table 1, entry 12).
Recently, we have developed an enantioselective hydro-
genation of a-phthalimide ketones with Pd(CF3CO2)2/
(R,R)-Me-DUPHOS system.8 Herein, we report our re-
sults for the homogeneous asymmetric hydrogenation of
Next, some commercially available chiral bidentate phos-
phine ligands (Figure 2) were also tested for the hydro-
genation of 1a under the same conditions (Table 2).
Obviously, electron-rich ligands led to full conversions
(Table 2, entries 2, 4, 6). High enantioselectivities were
SYNLETT 2006, No. 8, pp 1189–1192
1
5.
0
5.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-939712; Art ID: W31505ST
© Georg Thieme Verlag Stuttgart · New York

1190
Y.-Q. Wang, Y.-G. Zhou
LETTER
Table 1 Optimization of Reaction Conditionsa
Table 2 Ligand Screening for the Hydrogenation of Imines 1a
P(O)Ph2
N
P(O)Ph2
P(O)Ph2
P(O)Ph2
HN
N
HN
Pd(CF3CO2)2/Ligand
2 (1000 psi), TFE
Pd(CF3CO2)2/(R)-SynPhos
H
2a: R = H
2b: R = Me
H2, solvent
1a: R = H
1b: R = Me
1a
2a
R
R
Entry
1
Pd precursor
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CF3CO2)2
Pd(CH3CO2)2
Pd(OTf)2
Solvent
TFE
Yield (%)b ee (%)c
Entry
Substrate Ligand
Yield (%)b ee (%)c
Configura-
tiond
80 (85)
<5
94.6
–
1
1a
1a
1a
1a
1a
1a
1b
1b
L-2
L-3
L-4
L-5
L-5
L-6
L-5
L-5
54
96
12
98
33
93
35
93
95.8
95.1
95.9
96.0
93.0
28.0
95.4
96.6
R
2
i-PrOH
EtOH
MeOH
THF
2
R
3
<5
–
3
R
4
<5
–
4
S
5
<5
–
5e
6
S
6
CH2Cl2
toluene
TFE
<5
–
R
7
<5
–
7
S
8d
9
79
93.5
94.6
91.8
–
8f
S
TFE
82
a Unless otherwise stated, reactions were performed in TFE on a 0.2
mmol scale: Pd(CF3CO2)2 (2 mol%), ligand (2.4 mol%), H2 (1000
psi), r.t., 8 h.
10e
11e
12f
TFE
37
PdCl2
TFE
7
b Isolated yields.
c Determined by chiral HPLC analysis.
d Determined by comparison of the sign of the optical rotation with
literature data.
Pd(CF3CO2)2
TFE
85 (>95)
94.2
a Unless otherwise stated, reactions were performed on a 0.2 mmol
scale: Pd precursor (2 mol%), (R)-SYNPHOS (2.4 mol%), H2 (600
psi), 8 h.
e Reaction temperature: 0 °C.
f 4 Å MS (50 mg) was added.
b Isolated yields; conversions are shown in parentheses.
c Determined by chiral HPLC analysis.
d The reaction was carried out in an oil bath at 50 °C.
e Pure complex (2 mol%) was used and no extra ligand was added.
f Higher H2 pressure applied (1000 psi).
ee of 95.4% resulted. Fortunately, we found that addition
of 4 Å molecular sieves gave almost complete conversion
with similar ee values (Table 2, entries 7 vs 8).13 We
believe that 4 Å molecular sieves may remove traces of
water, which appear to make the substrate and catalyst
unstable.
obtained using bisphosphine ligands with biphenyl and
binaphthyl motifs (Table 2, entries 1–4), and the best re-
sult (96.0% ee) was achieved with (S)-SEGPHOS L-5
(Table 2, entry 4). Lowering the reaction temperature to
0 °C resulted in a decreased conversion (Table 2, entry 5).
With electron-rich imine 1b as the substrate (entry 7),
only a moderate conversion was obtained but an excellent
Under optimized conditions [Pd(OCOCF3)2/(S)-
SEGPHOS, 4 Å MS, TFE], a variety of substituted N-
diphenylphosphinyl imines 1b–j were subjected to asym-
metric hydrogenation (Table 3).14,15 Both electron-defi-
cient (Table 3, entries 3 and 4) and electron-rich (Table 3,
entries 2, 5–7) aryl imines can be hydrogenated with high
enantioselectivities. It is noticeable that the enantioselec-
tivity of the hydrogenation reaction for aryl imines with
an electron-donating substituent is better than those with
electron-withdrawing substituents (Table 3, entries 2 and
5 vs 3 and 4). For meta-methoxy-substituted aryl imines
1f, a high enantioselectivity was also obtained (Table 3,
entry 6). ortho-Methoxy-substituted aryl imines 1g gave
the highest ee of 98.6% (Table 3, entry 7). Imine 1j bear-
ing a furyl group gave moderate conversion with 87% ee
(Table 3, entry 10). Imines 1h and 1i also gave good
asymmetric induction (Table 3, entries 8 and 9), albeit
with slightly lower activity due to steric effects. It should
be noted that the enantioselectivity was comparable to that
obtained with rhodium and iridium complex catalysts.4,10
O
O
O
PPh2
PPh2
PPh2
PPh2
MeO
MeO
PPh2
PPh2
O
L-1 (R)-SYNPHOS
L-2 (R)-BINAP
L-3 (R)-MeO-BIPHEP
Cl
O
P
P
O
O
MeO
MeO
PPh2
PPh2
PPh2
PPh2
O
Cl
L-5 (S)-SEGPHOS
L-6 (R,R)-Me-DUPHOS
L-4
Figure 1
Synlett 2006, No. 8, 1189–1192 © Thieme Stuttgart · New York

LETTER
Enantioselective Pd-Catalyzed Asymmetric Hydrogenation of N-Diphenylphosphinyl Ketimines
1191
Table 3 Asymmetric Hydrogenation of N-Diphenylphosphinyl
Imines Catalyzed by a Pd(OCOCF3)2/(S)-SEGPHOS Systema
(3) (a) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008.
(b) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998.
(c) Rossen, K. Angew. Chem. Int. Ed. 2001, 40, 4611.
(d) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029.
(4) For reviews on the asymmetric hydrogenation of imines,
see: (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99,
1069. (b) Brunel, J. M. Recent Res. Dev. Org. Chem. 2003,
7, 155. (c) Liu, P.; Jiang, H.-F. Chin. J. Org. Chem. 2004,
24, 1317.
P(O)Ph2
P(O)Ph2
Pd(CF3CO2)2/(S)-SEGPHOS
N
HN
H2, TFE, 4 Å MS (50 mg)
Ar
R
Ar
R
2
1
Entry Ar
R
Conversion
(%)b
ee (%)c
(5) Recent literature on heterogeneous Pd asymmetric
hydrogenation: (a) Studer, M.; Blaser, H.-U.; Exner, C. Adv.
Synth. Catal. 2003, 345, 45. (b) Tungler, A.; Fogassy, G. J.
Mol. Catal. A: Chem. 2001, 173, 231. (c) Blaser, H.-U.;
Indolese, A.; Schnyder, A.; Steiner, H.; Studer, M. J. Mol.
Catal. A: Chem. 2001, 173, 3. (d) Li, C. Catal. Rev. 2004,
46, 419. (e) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard,
R.; Lehmann, C. W. Angew. Chem. Int. Ed. 2004, 43, 2850.
(f) Raynor, S. A.; Thomas, J. M.; Raja, R.; Johnson, B. F. G.;
Bell, R. G.; Mantle, M. D. Chem. Commun. 2000, 1925.
(6) (a) Abe, H.; Amii, H.; Uneyama, K. Org. Lett. 2001, 3, 313.
(b) Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J. Org.
Chem. 2004, 69, 5132.
1d
2
Ph
Me (1a)
Me (1b)
Me (1c)
Me (1d)
Me (1e)
Me (1f)
Me (1g)
Et (1h)
>95 (98)
>95 (93)
>95 (87)
94 (90)
96.0
96.6
94.0
94.2
96.0
96.0
98.6
86.7
92.8
87.0
4-MeC6H4
4-FC6H4
4-ClC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
C6H5
3
4
5
>95 (96)
>95 (97)
91 (80)
6
7e
8e
9e
10e
(7) Nanayakkara, P.; Alper, H. Chem. Commun. 2003, 2384.
(8) Wang, Y.-Q.; Lu, S.-M.; Zhou, Y.-G. Org. Lett. 2005, 7,
3235.
>95 (93)
77 (70)
2-Naphthyl
2-Furyl
Me (1i)
Me (1j)
(9) (a) Krzyzanowska, B.; Stec, W. J. Synthesis 1982, 270.
(b) Masumoto, S.; Usuda, H.; Suzuki, M.; Kainai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634.
(10) Asymmetric hydrogenation of N-diphenylphosphinyl
imines: (a) Rh complex: Spindler, F.; Blaser, H.-U. Adv.
Synth. Catal. 2001, 343, 68. (b) Ir complex: Jiang, X.-B.;
Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau, A.
L. L.; Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G.
Org. Lett. 2003, 5, 1503.
62 (29)
a Reactions were performed in TFE on a 0.2-mmol scale:
Pd(CF3CO2)2 (2 mol%), ligand (2.4 mol%), H2 (1000 psi), r.t.
b Conversions were determined by 1H NMR spectroscopy; isolated
yields are shown in parenthesis.
c Determined by chiral HPLC analysis.
d No MS added.
e Catalyst (4 mol%).
(11) Asymmetric reduction of N-diphenylphosphinyl imines
without hydrogen: (a) Yamada, T.; Nagata, T.; Sugi, K.;
Yorozu, K.; Ikeno, T.; Ohtsuka, Y.; Miyazaki, D.;
Mukaiyama, T. Chem. Eur. J. 2003, 9, 4485. (b) Hutchins,
R. O.; Magid, A. A.; Stercho, Y. P.; Wambsgans, A. J. Org.
Chem. 1987, 52, 702. (c) Lipshutz, B. H.; Shimizu, H.
Angew. Chem. Int. Ed. 2004, 43, 2228.
(12) N-(Diphenylphosphinyl)amines 2 obtained by addition of
diorganozinc to aldimines: Boezio, A. A.; Pytkowicz, J.;
Côté, A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125,
14260.
In conclusion, a highly enantioselective homogeneous
hydrogenation of N-diphenylphosphinyl imines was de-
veloped using a chiral Pd complex in TFE; up to 98.6% ee
was obtained, which provided a convenient route to chiral
amines. Our ongoing experiments are focused on explor-
ing the palladium catalyzed hydrogenation mechanism
and other asymmetric hydrogenation reactions.
(13) A series of additives were tested in the reaction of 1b: 3 Å
MS (conversion: >95%, 96.4% ee), 5 Å MS (conversion:
72%, 96.4% ee), Na2SO4 (conversion: 64%, 96.4% ee).
(14) Asymmetric Hydrogenation; Typical Procedure. (S)-
SEGPHOS (2.9 mg, 0.0048 mmol) and Pd(CF3CO2)2 (1.3
mg, 0.004 mmol) were placed in a dried Schlenk tube under
a nitrogen atmosphere, and degassed anhydrous acetone was
added. The mixture was stirred at r.t. for 1 h. The solvent was
removed under vacuum to give the catalyst. This catalyst
was placed in a nitrogen-filled glove box and dissolved in
anhyd TFE (1 mL). To a mixture of 1a and 4 Å MS, the
catalyst solution was added, and then the mixture was
transferred to an autoclave. The hydrogenation was
performed at r.t. under H2 (1000 psi) for 8–12 h. The
hydrogen was carefully released and the solvents were
removed. Conversion was determined by 1H NMR
spectroscopy. The ee was determined by HPLC after
purification on silica gel (hexanes–EtOAc–Et3N, 1:2:0.02).
The absolute configuration of 2a was determined by
measurement of its optical rotation. N-Diphenylphosphinyl
imines 1 were prepared according to the literature.9
Racemates of N-(diphenylphosphinyl)amines were prepared
Acknowledgment
We are grateful to the National Science Foundation of China and the
Talented Scientist Program, Chinese Academy of Sciences for
financial support.
References and Notes
(1) (a) Comprehensive Asymmetric Catalysis; Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York, 1999.
(b) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-
VCH: New York, 2000, 2nd ed.
(2) (a) Tsuji, J. Palladium Reagents and Catalysis; John Wiley
& Sons: Chichester, 2004. (b) Negishi, E. Handbook of
Organopalladium Chemistry for Organic Synthesis; Wiley:
Hoboken NJ, 2002. (c) Heck, R. F. Pd Reagents in Organic
Synthesis; Academic: New York, 1985. (d) Tietze, L. F.; Ila,
H.; Bell, H. P. Chem. Rev. 2004, 104, 3453.
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1192
Y.-Q. Wang, Y.-G. Zhou
LETTER
by reduction of the corresponding imines using NaBH4 in
THF. For the preparation of complexes and other
experimental details, see reference 8.
Hz, 1 H), 4.33–4.40 (m, 1 H), 7.24 (dd, J = 8.5, 23.0 Hz, 4
H), 7.37–7.47 (m, 6 H), 7.79 (dd, J = 7.0, 12.0, 2 H), 7.90
(dd, J = 6.9, 11.9 Hz, 2 H).
(15) Compound 1c: white solid. 1H NMR (400 MHz, CDCl3):
d = 2.95 (d, J = 1.8 Hz, 3 H), 7.12–7.17 (m, 2 H), 7.43–7.45
(m, 6 H), 7.94–7.99 (m, 4 H), 8.09–8.12 (m, 2 H). 13C NMR
(100 MHz, CDCl3): d = 23.1 (d, J = 12.3 Hz), 115.8 (d,
J = 21.7 Hz), 128.6 (d, J = 12.3 Hz), 130.6 (d, J = 8.9 Hz),
131.7, 131.8, 134.8 (d, J = 130.2 Hz), 135.9 (d, J = 25.8 Hz),
165.7 (d, J = 252.7 Hz), 180.2 (d, J = 7.0 Hz). 31P NMR (162
MHz, CDCl3): d = 19.1. HRMS (ESI): m/z calcd for
C20H18FNOP [M + H+]: 338.1105; found: 338.1082.
Compound 1f: white solid. 1H NMR (400 MHz, CDCl3):
d = 2.95 (d, J = 2.1 Hz, 3 H), 3.88 (s, 3 H), 7.10 (m, 1 H),
7.39–7.46 (m, 7 H), 7.64 (d, J = 2.4 Hz, 2 H), 7.95–8.00 (m,
4 H). 13C NMR (100 MHz, CDCl3): d = 23.3 (d, J = 12.4
Hz), 55.6, 113.6, 117.9, 120.7, 128.6 (d, J = 12.4 Hz), 129.7,
131.6, 131.7 (d, J = 9.0 Hz), 134.8 (d, J = 130.3 Hz), 141.0
(d, J = 23.9 Hz), 159.8, 181.5 (d, J = 7.5 Hz). 31P NMR (162
MHz, CDCl3): d = 19.3. HRMS (ESI): m/z calcd for
C21H21NO2P [M + H+]: 350.1304; found: 350.1297.
Compound 1g: white solid. 1H NMR (400 MHz, CDCl3):
d = 2.89 (d, J = 2.0 Hz, 3 H), 3.82 (d, J = 2.4 Hz, 3 H), 6.93
(d, J = 8.3 Hz, 1 H), 7.00 (s, 1 H), 7.40–7.45 (m, 7 H), 7.63
(dd, J = 1.7, 7.6 Hz, 1 H), 7.93–7.99 (m, 4 H). 13C NMR (100
MHz, CDCl3): d = 28.3 (d, J = 13.6 Hz), 55.5, 111.6, 120.6,
128.4 (d, J = 12.3 Hz), 129.9, 131.4, 131.8 (d, J = 8.9 Hz),
132.3, 134.9 (d, J = 129.2 Hz), 158.0, 186.0 (d, J = 7.6 Hz).
31P NMR (162 MHz, CDCl3): d = 18.5. HRMS (ESI): m/z
calcd for C21H21NO2P [M + H+]: 350.1304; found: 350.1288.
Compound 2a: white solid; 95.3% ee (R); [a]D26 +38.3 (c
0.54, EtOH); Rf 0.14 (PE–EtOAc, 2:1); HPLC (Chiralpak
AS-H column, hexane–i-PrOH, 20:80, 1.0 mL/min, 254
nm): tR 12.9 min (R), tR 24.4 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.58 (d, J = 6.7 Hz, 3 H), 3.17 (dd, J = 5.9, 9.1
Hz, 1 H), 4.36–4.43 (m, 1 H), 7.26–7.45 (m, 11 H), 7.80–
7.85 (m, 2 H), 7.89–7.93 (m, 2 H).
Compound 2e: white solid; 96.0% ee (S); [a]D8 –66.4 (c
1.30, MeOH); HPLC (Chiralpak AS-H column, hexane–i-
PrOH, 80:20, 1.0 mL/min, 254 nm): tR 15.9 min (R), tR 26.8
min (S). 1H NMR (400 MHz, CDCl3): d = 1.55 (d, J = 6.7
Hz, 3 H), 3.12 (dd, J = 5.9, 9.4 Hz, 1 H), 3.80 (s, 3 H), 4.31–
4.41 (m, 1 H), 6.85 (d, J = 8.7 Hz, 2 H), 7.21 (d, J = 8.7 Hz,
2 H), 7.37–7.48 (m, 6 H), 7.81–7.91 (m, 4 H).
Compound 2f: white solid; 96.0% ee (S); [a]D8 –52.1 (c 1.32,
MeOH); Rf 0.38 (PE–EtOAc, 1:1); HPLC (Chiralpak AS-H
column, hexane–i-PrOH, 80:20, 1.0 mL/min, 254 nm):
tR 14.5 min (R), tR 29.4 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.57 (d, J = 6.8 Hz, 3 H), 3.22 (dd, J = 5.9, 9.5
Hz, 1 H), 3.78 (s, 3 H), 4.31–4.39 (m, 1 H), 6.82–6.88 (m, 3
H), 7.21–7.23 (m, 1 H), 7.36–7.47 (m, 6 H), 7.80–7.93 (m, 4
H).
Compound 2g: white solid; 98.6% ee (S); [a]D8 –22.1 (c
1.13, MeOH); Rf 0.33 (PE–EtOAc, 1:1). HPLC (Chiralpak
AS-H column, hexane–i-PrOH, 80:20, 1.0 mL/min, 254
nm): tR 11.9 min (R), tR 21.3 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.50 (d, J = 6.8 Hz, 3 H), 3.69 (s, 3 H), 3.87 (dd,
J = 8.0, 10.5 Hz, 1 H), 4.36–4.43 (m, 1 H), 6.78–6.82 (m, 2
H), 6.97 (s, 1 H), 7.19 (t, J = 7.7 Hz, 1 H), 7.33–7.38 (m, 6
H), 7.72 (dd, J = 7.3, 11.9 Hz, 2 H), 7.79 (dd, J = 7.1, 11.8
Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 25.1, 49.6, 55.4,
111.2, 121.0, 128.3 (d, J = 7.0 Hz), 128.5, 131.7, 131.8,
128.1 (d, J = 108.6 Hz), 131.7, 131.8, 132.0 (d, J = 9.3 Hz),
132.8 (d, J = 9.4 Hz), 133.0, 133.1, 133.8 (d, J = 119.7 Hz),
157.0. 31P NMR (162 MHz, CDCl3): d = 22.9. HRMS (ESI):
m/z calcd for C21H23NO2P [M + H+], 352.1461; found,
352.1451.
Compound 2h: white solid; 86.7% ee (S); [a]D8 –38.5 (c
1.26, MeOH); Rf 0.31 (PE–EtOAc, 1:1); HPLC (Chiralpak
AS-H column, hexane–i-PrOH, 80:20, 1.0 mL/min, 254
nm): tR 9.6 min (R), tR 17.7 min (S). 1H NMR (400 MHz,
CDCl3): d = 0.79 (t, J = 7.4 Hz, 3 H), 1.80–1.89 (m, 1 H),
1.97–2.04 (m, 1 H), 3.25 (dd, J = 6.4, 9.4 Hz, 1 H), 4.08–
4.11 (m, 1 H), 7.14–7.16 (m, 2 H), 7.23–7.33 (m, 5 H), 7.42–
7.44 (m, 4 H), 7.73–7.87 (m, 4 H).
Compound 2b: white solid; 96.6% ee (S); [a]D8 –66.5 (c
1.08, MeOH); Rf 0.22 (PE–EtOAc, 2:1); HPLC (Chiralpak
AS-H column, hexane–i-PrOH, 80–20, 1.0 mL/min, 254
nm): tR 11.4 min (R), tR 15.8 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.56 (d, J = 6.8 Hz, 3 H), 2.34 (s, 3 H), 3.14–
3.17 (m, 1 H), 4.32–4.39 (m, 1 H), 7.15 (dd, J = 8.0, 20.4 Hz,
4 H), 7.37–7.48 (m, 6 H), 7.81–7.91 (m, 4 H).
Compound 2i: white solid; 92.8% ee (S); [a]D8 –77.8 (c 1.02,
MeOH); Rf 0.39 (PE–EtOAc, 1:1); HPLC (Chiralpak AS-H
column, hexane–i-PrOH, 80:20, 1.0 mL/min, 254 nm):
tR 21.6 min (R), tR 27.7 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.66 (d, J = 6.7 Hz, 3 H), 3.27–3.31 (m, 1 H),
4.51–4.61 (m, 1 H), 7.32–7.33 (m, 2 H), 7.43–7.48 (m, 7 H),
7.65 (s, 1 H), 7.80–7.83 (m, 5 H), 7.93 (m, 2 H).
Compound 2c: white solid; 94.0% ee (S); [a]D8 –41.9 (c
1.04, MeOH); Rf 0.18 (PE–EtOAc, 2:1); HPLC (Chiralpak
AS-H column, hexane–i-PrOH, 80:20, 1.0 mL/min, 254
nm): tR 10.0 min (R), tR 27.0 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.55 (d, J = 6.8 Hz, 3 H), 3.11 (dd, J = 5.9, 9.2
Hz, 1 H), 4.35–4.42 (m, 1 H), 6.98 (t, J = 8.7 Hz, 2 H), 7.23–
7.25 (m, 2 H), 7.36–7.37 (m, 2 H), 7.44–7.46 (m, 4 H), 7.78–
7.81 (m, 2 H), 7.88–7.92 (m, 2 H).
Compound 2j: white solid, 87.0% ee (S), [a]D8 –42.1 (c 0.60,
CH2Cl2); Rf 0.34 (PE–CH2Cl2,1:4); HPLC (Chiralpak AS-H
column, hexane–i-PrOH, 80:20, 1.0 mL/min, 254 nm):
tR 12.1 min (R), tR 17.0 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.60 (d, J = 6.8 Hz, 3 H), 3.19 (dd, J = 6.6, 10.3
Hz, 1 H), 4.38–4.44 (m, 1 H), 6.13 (d, J = 3.2 Hz, 1 H), 6.28
(dd, J = 1.9, 3.2 Hz, 1 H), 7.35 (m, 1 H), 7.42–7.49 (m, 6 H),
7.87–7.95 (m, 4 H).
Compound 2d: white solid; 94.2% ee (S); [a]D8 –73.4 (c
1.14, MeOH); Rf 0.33 (PE–EtOAc, 1:1); HPLC (Chiralpak
AS-H column, hexane–i-PrOH, 80:20, 1.0 mL/min, 254
nm): tR 11.4 min (R), tR 26.3 min (S). 1H NMR (400 MHz,
CDCl3): d = 1.55 (d, J = 6.8 Hz, 3 H), 3.17 (dd, J = 5.7, 9.5
Synlett 2006, No. 8, 1189–1192 © Thieme Stuttgart · New York