A straightforward access to pyrrolidine-based ligands for asymmetric synthesis

Article abstract of DOI:10.1016/j.tetasy.2010.09.015

A straightforward and flexible method for the preparation of ligands based on the pyrrolidine scaffold is presented. The synthetic strategy involves a diastereoselective allylation of phenylglycinol-derived imines, followed by a cyclization promoted by a

Full text of DOI:10.1016/j.tetasy.2010.09.015

Tetrahedron: Asymmetry 21 (2010) 2505–2511
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A straightforward access to pyrrolidine-based ligands for asymmetric synthesis
⇑
Pierre-Olivier Delaye, M’hamed Ahari, Jean-Luc Vasse , Jan Szymoniak
Institut de Chimie Moléculaire de Reims, CNRS-UMR 6229, Université de Reims Champagne-Ardenne, BP 1039, 51687 Reims Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward and flexible method for the preparation of ligands based on the pyrrolidine scaffold is
presented. The synthetic strategy involves a diastereoselective allylation of phenylglycinol-derived imi-
nes, followed by a cyclization promoted by a hydrozirconation/halogenation sequence. Enantioselectivi-
ties of up to 84% ee in the asymmetric allylic allylation were obtained using these ligands.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 30 August 2010
Accepted 21 September 2010
Available online 27 October 2010
1. Introduction
sequential hydrozirconation/iodination methodology to enantio-
merically pure homoallylic amines. The configuration of the
The development of versatile and general asymmetric methods
for elaborating upon heterocyclic scaffolds is a key feature in mod-
ern ligand design for metal-catalyzed transformations.1 Although,
several P,P-ligands are known to induce high levels of asymmetric
induction on several metal-catalyzed processes, P,N-ligands occu-
py a growing place.2 In fact, the electronic dissymmetry in such li-
gands has, in some cases, a great impact on the asymmetric course
of a reaction.3 Among N-heterocycle-based ligands, the pyrrolidine
skeleton has emerged as one the most efficient backbones for gen-
erating a discriminative environment around the metal.4
We have recently described two strategies for the synthesis of
enantiomerically pure 2-substituted pyrrolidines. The first one in-
volves a tandem hydrozirconation/Lewis acid-mediated cyclization
applied to N-allyloxazolidines.5 The second, consists of a hydrozirc-
onation/iodination sequence starting from homoallylic amines.6
These two approaches are general and stereo-complementary
leading stereoselectively to enantiomeric pyrrolidines after the re-
moval of the chiral inductor residue (Scheme 1).
homoallylic amines could be controlled by the diastereoselective
allylmetallation of the corresponding (R)-phenylglycinol-derived
imine (Fig. 1).
1)
2) RCHO
Br
1) RCHO
R
NH2
Ph
HO
HN
R
N
Br
2)
In
O
(R)
HO
Ph
Ph
1) Cp2Zr(H)Cl
2) I2, NEt3
1) Cp2Zr(H)Cl
2) TiCl4
C-C bond-
forming
C-Nbond-
forming
R
R
N
N
R
N
R
N
HO
H
H
HO
Ph
Ph
Scheme 1.
Herein we report the synthesis of simple phosphino-
pyrrolidines prepared according to the C–N bond-forming strategy.
Cyclisation
Allylation
N
2. Results and discussion
L
N
NH
N
Ph
Ph
Ph
Efficient P,N-ligands, ferrocene-based amino-phosphines, pyri-
dine-phosphines, and pyrrolidine-phosphines have been proved
to afford a high level of asymmetric induction in palladium-
catalyzed allylic substitution.7 Therefore, we decided to prepare
different ligands combining a 2-substituted pyrrolidine and a
phosphine moiety. Access to these ligands was envisioned by link-
ing the phosphine unit to the 1 or the 2-position of the pyrrolidine.
The pyrrolidine precursors would be prepared by applying the
N
OH
OH
OH
L
L = N, S, P
Figure 1.
The diastereoselective allylation of chiral imines has been
widely described in the literature and can be carried out either
with Grignard reagents or under Barbier conditions with several
metals.8 Among the chiral auxiliaries, phenylglycinol appears to
be one of the more efficient ones in terms of stereoselectivity.9
⇑
Corresponding author.
E-mail address: jean-luc.vasse@univ-reims.fr (J.-L. Vasse).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.09.015

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P.-O. Delaye et al. / Tetrahedron: Asymmetry 21 (2010) 2505–2511
Moreover, different conditions could be employed to remove the
chiral auxiliary residue.
whereas the use of allylmagnesium bromide as an allyl promotor
resulted in a mixture of diastereomers, the use of indium in Barbier
conditions led to the single stereoisomer 1c in good yield. The
hydrozirconation/iodination conditions were applied to afford the
expected pyrrolidine 2c. Subsequent hydrogenolysis gave the
N-free pyrrolidine 3c which constitutes the scaffold for the ligand
design. The reductive amination applied to 3c and 2-(diphenyl-
phosphinyl) benzaldehyde in the presence of NaBH(OAc)3 provides
L3.
We next focused our attention on the functionalization of the
ferrocenyl fragment by the stereodirected lithiation of pyrrolidine
4c, prepared from 2c. Based on the pioneering work of Ugi,12 sev-
eral diastereoselective metallation procedures of the ferrocenyl
moiety were reported to provide P,P-,13 P,S-,14 and P,N-ligands.15
Among them, Guiry et al. described the preparation of N,O-ferroce-
nyl pyrrolidine ligands via the diastereoselective lithiation of 4c
using sec-BuLi as the base and trapping with symmetrical ke-
tones.16 A highly diastereoselective preparation of ligand L6 has
been mentioned,17 however no details are given.
We first decided to prepare a simple pyrrolidine bearing a 2-
diphenylphosphinyl group at the 2-position of the heterocycle.
We have previously reported the preparation of a pyrrolidine bear-
ing 2-bromophenyl at the required position, which prompted us to
incorporate the diphenylphosphine via a bromine/lithium ex-
change. However, the synthetic strategy had to be slightly modi-
fied with respect to that described in Scheme 1. In fact, the
removal of the chiral auxiliary could not be achieved through
hydrogenolysis, but under oxidative conditions prior to cyclization,
using Pb(OAc)4. The corresponding amine was isolated in its N-Boc
protected form 2a to facilitate purification.10 Subsequent N-
methylation and Boc removal gave the amine intermediate 3a
which underwent the hydrozirconation/iodination-sequence to af-
ford the desired pyrrolidine 4a. Further bromine/lithium exchange,
followed by the addition of chlorodiphenylphosphine, afforded the
expected ligand L1 (Scheme 2).
Br
Br
According to this procedure, PhSSPh, (EtO)2PCl, and Ph2PCl were
employed as electrophiles. The reaction typically proceeded with a
4:1 diastereomeric ratio. The major isomers were isolated in a pure
form after column chromatography, providing the corresponding
S-N ligand and P-N ligands, L4, L5, and L6, respectively (Scheme 4).
Finally, in order to obtain the opposite planar configuration, the
locking of the first metallation position with a silyl group was
achieved prior to the phosphine incorporation. Thus, TMSCl was
employed as the first electrophile to give 5c. The addition of a sec-
ond equivalent of the base and reaction with PP2Cl afforded the de-
sired ligand L8 after TBAF-mediated silyl removal.
Br
1) Pb(OAc)4
1) NaH, CH3I
NH
NH
NH
Boc
2a
2) NH2OH.HCl
3) (Boc)2O
2) TFA
65%
Ph
1a
3a
60%
OH
Cp2Zr(H)Cl
then, I2, Et3N
n-BuLi,
then PPh2Cl
Br
PPh2
N
N
83%
65%
4a
L1
Scheme 2.
The preparation of a ligand containing the 2-pyridinyl entity
was planned next. In this case, the protection of the amine function
with a labile group was necessary. However, a deactivating protec-
tion had to be avoided, since detrimental pyridine quaternarisation
would occur instead. Thus, we chose the N-trityl protection strat-
egy by preparing 2b. In this case, the free pyrrolidine 3b was di-
rectly obtained in 69% yield after aqueous work-up.11 Additional
coupling with PPh2Cl followed by BH3 trapping afforded phos-
phino-pyridine L2ꢀBH3 (Scheme 3).
Ph
H
N
N
R
1) Cp2Zr(H)Cl
2) I2, Et3N
N
Br
In, MeOH
Fe
Fe
OH
Ph
OH
Fe
1c
2c, R = (R)CHPh-CH2OH
3c, R = H
H2, Pd(OH)2/C
PPh2
CHO
N
PPh2
1) HCHO
2) NaBH4
94%
N
Fe
3c
N
Fe
N
1) Pb(OAc)4
Br
N
, In
NH2
NaBH(OAc)3
71%
NH
4c
2) NH2OH.HCl
L3
2b
ref 8a
87%
Ph
dr 96 : 4
N
1) s-BuLi
90%
OH
2) E+
Tr-Cl, Et3N
N
Ph
1b
1) TBDMSCl
2) separation
3) TBAF
OH
E
1) s-BuLi
N
1b dr 9 9> 1
5c
N
Fe
PPh2
75%
2) PPh2Cl
3) TBAF
NH
Tr
E = SPh, L4, 71%
Fe
E = P(OEt)2, L5, 70%
L7
E = PPh2, L , 67%
6
36%
E = SiMe3, 5c, 63%
N
1) PPh2Cl, Et3N
N
1) Cp2Zr(H)Cl
N
Ph2P
N
H
2) BH3.SMe2
3) DABCO
Scheme 4.
2) I2, Et3N
69%
BH3
3b
L2·BH3
With these ligands in hand, the palladium-catalyzed asymmet-
ric allylic substitution was tested next. This reaction is widely de-
scribed in the literature and has emerged as one of the most
powerful C–C, C–N, and C–O asymmetric bond-forming pro-
cesses.18 The asymmetric allylic substitution of dimethyl malonate
with rac-1,3-diphenylpropen-1-yl acetate was then investigated, in
the presence of allylpalladium-chloride dimer as the palladium
source and ligands L1–L7 (Table 1).
62%
Scheme 3.
From the efficient ligands, ferrocenylphosphines have been pro-
ven to induce a high level of asymmetric induction in catalytic
transformations.7a,b For that reason, we decided to prepare a pyr-
rolidine containing the ferrocenyl unit at the 2-position. The syn-
thesis started with the stereodetermining allylmetallation of the
corresponding (R)-phenylglycinol-derived imine. At this stage,
By using these ligands, a complete substrate conversion was
achieved within 4 h at room temperature with a catalyst loading

P.-O. Delaye et al. / Tetrahedron: Asymmetry 21 (2010) 2505–2511
2507
Table 1
sequence. The flexibility of the method allows the incorporation
of arylic, pyridinic, or ferrocenic unit at the 2-position of the pyr-
rolidine and subsequent functionalization providing N,S- and N,P-
ligands. Tested in an asymmetric allylic substitution, this series
of ligands gives moderate to good enantioselectivities, although
the methodology offers various opportunities for ligand design in
the asymmetric catalysis.
Palladium-catalyzed asymmetric allylic alkylation
MeO2C
CO2Me
OAc
MeO2C
Ph
CO2Me
Ph
[PdCl(π-C3H5)]2, L
BSA, KOAccat.
Ph
Ph
Entrya
Ligand
Time (h)
T (°C)
Conversion (%)
eeb (%)
4. Experimental
1
2
3
5
6
7
8
9
10
L1
L2c
L2d
L3
L4
L5
L6
L6
L7
4
8
8
4
72
4
4
8
4
20
20
20
20
20
20
20
0
100
100
90
100
100
100
100
100
100
63 (R)
84 (S)
84 (S)
58 (R)
77 (R)
75 (R)
78 (R)
78 (R)
32 (R)
All the reactions were conducted under an atmosphere of argon.
Prior to use, THF and Et2O were distilled under argon from sodium
benzophenone, ketyl, Et3N, and CH2Cl2 were distilled under argon
from CaH2, Cp2Zr(H)Cl was prepared according to known proce-
dure,21 reagents were used as received. 1H, 13C, and 31P NMR spec-
tra were recorded in CDCl3, unless specified, on a Brucker AC-250.
Mass spectra were recorded on a Micromass Q-TOF micro MS
spectrometer.
20
a
The reaction was conducted under Ar at rt using 2 equiv of methyl malonate,
2.5 equiv of BSA, and was initiated by adding a catalytic amount of KOAc.
b
Determined by HPLC using OD-H-chiralpak column.
c
L2 was generated in situ by treating L2ꢀBH3 with DABCO (1 equiv) for 6 h at
4.1. General procedure for the preparation of homoallylic
amines (Procedure A)
80 °C in toluene prior to the catalytic reaction.
d
L2 was generated in situ from L2ꢀBH3 using Pd(OAc)2 as the palladium source.
To a solution of (R)-phenylglycinol-derived imine (1 mmol) and
allylbromide (260 lL, 3 mmol) in MeOH (5 mL) were added small
of 5 mol % (entries 1–5 and 7–10), except in the case of an N,S-
ligand L4, which required 72 h for going to completion. Moderate
to good enantioselectivities of up to 84% (ligand L2, entries 2 and
3) were observed. In the case of ferrocene-containing ligands, a
more efficient discrimination was observed when combining the
(R)-configuration at the pyrrolidine junction to (p-R)-configuration
of the ferrocenyl fragment, L3, L4, L5, and L6 versus L7 (entries 5–9
vs entry 10).
amounts of In (113 mg, 1 mmol) at rt. The reaction mixture was
stirred at rt for 6 h and then a saturated aqueous solution of NaH-
CO3 (5 mL) was added. The resulting mixture was filtered and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in AcOEt (30 mL), washed with H2O (10 mL), dried over
MgSO4, filtered and the solvent was removed under reduced pres-
sure. The residue was purified by flash chromatography on silica
gel eluting with a mixture of PE/AcOEt to give the corresponding
amine 1.
In the cases of the P,N-ligands, the nucleophilic attack is known
to occur predominantly at the allylic termini trans to the phospho-
rus of the allyl–palladium complex.19
Therefore, we assumed the predominant formation and reactiv-
ity of the allyl–palladium complex B over A (Fig. 2) to account for
the observed enantioselectivity when using L2 as the ligand.
Firstly, A suffers from steric interactions, thus favouring the forma-
tion of B. Secondly, the difference in reactivity may be deduced
from the more pronounced congestion in the palladium–olefin
complex A0 deriving from A, favoring the rotation of the allyl frag-
ment from B to B0,20 a precursor of the (S)-enantiomer.
4.1.1. (R)-[(R)-1-(2-Bromophenyl)but-3-enylamino)-2-
phenyle- thanol 1a
Yield = 77%. Orange oil; ½a D20
ꢁ
¼ ꢂ37:2 (c 1, CH2Cl2); 1H NMR
(250 MHz, CDCl3): d 7.46 (1H, d, J = 7.9 Hz), 7.40–7.19 (7H, m),
7.10 (H, m), 7.03 (1H, d, J = 7.8 Hz), 5.75 (1H, m), 5.08 (d,
J = 19.0 Hz, 1H), 5.06 (1H, d, J = 9.1 Hz), 4.32 (1H, t, J = 6.4 Hz),
3.82–3.70 (1H, m), 3.58 (1H, dd, J = 10.0, 5.5 Hz), 2.46 (2H, m),
2.14 (1H, br s); 13C NMR (CDCl3, 62.5 MHz): d 142.2, 141.0, 134.5,
132.6, 128.30, 128.25, 128.20, 127.30, 127.25, 127.1, 123.7, 117.8,
65.1, 61.5, 58.4, 40.6; HRMS-ESI: m/z [M+H]+ calcd for C18H21BrNO:
346.0807; found: 346.0814.
Pd
N
N
Pd
P
N
P
N
P
Ph
Pd
N
Ph
Ph
Ph
Nu
4.1.2. (R)-[(R)-1-Ferrocenylbut-3-enylamino)-2-phenylethanol 1c
Yield = 91%. Red oil.
½
a 2D0
ꢁ
¼ ꢂ57:0 (c 1, CH2Cl2); 1H NMR
Ph
Ph
P
N
Pd
P
(250 MHz, CDCl3): d 7.40–7.20 (5H, m), 5.67 (1H, m), 5.02–5.08
(2H, m), 3.95–4.15 (9H, m), 3.88 (1H, dd, J = 8.2, 4.3 Hz),
3.62–3.72 (2H, m), 3.46 (1H, t, J = 5.2 Hz), 2.43 (2H, m), 1.75 (2H,
br s); 13C NMR (62.5 MHz, CDCl3): d 141.0, 135.1, 128.6, 127.6,
127.1, 116.8, 92.3, 68.2, 67.2, 67.0, 66.6, 66.1, 65.7, 61.1, 53.0,
39.8; HRMS-ESI: m/z [M+H]+ calcd for: C22H26NOFe: 376.1364;
found: 376.1374.
N
Pd
Ph
Nu
Ph
B
A
Favored
Disfavored
MeO2C
Ph
P
CO2Me
N
Pd
Ph
N
Pd
P
Ph
CO2Me
B'
Ph
MeO2C
A'
(R)
4.1.3. (R)-2-Phenyl-[(R)-1-(pyrydin-2-yl)but-3-enylamino]-
(S)
ethanol 1b8a
Figure 2.
To
a solution of (R)-phenylglycinol-derived imine (3.43 g,
15.2 mmol) and allylbromide (2.2 mL, 25 mmol) in MeOH
(65 mL) were added small amounts of In (1.6 g, 14 mmol) at rt.
The reaction mixture was stirred at rt for 6 h and then a saturated
aqueous solution of NaHCO3 (25 mL) was added. The resulting
mixture was filtered and the filtrate was concentrated under re-
duced pressure. The residue was dissolved in AcOEt (50 mL),
3. Conclusion
In conclusion, a series of bidentate ligands, based on the 2-
pyrrolidine scaffold, have been synthesized. The pyrrolidine frame-
work was built via a sequential hydrozirconation/halogenation

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P.-O. Delaye et al. / Tetrahedron: Asymmetry 21 (2010) 2505–2511
washed with H2O (20 mL), dried over MgSO4, filtered, and the sol-
vent was removed under reduced pressure. The crude 1b (3.54 g,
87%, dr 96:4) was diluted into CH2Cl2 (50 mL), then Et3N, (2.4 mL,
17 mmol) and TBDMSCl (2.30 g, 15.2 mmol) were added succes-
sively at rt. After 6 h of stirring, water (25 mL) was added. The or-
ganic layer was dried over MgSO4, filtered and concentrated under
vacuum. The residue was purified by flash column chromatogra-
phy on silica gel eluting with a mixture of PE/AcOEt (90:10) to give
of Na2CO3 (10 mL). The organic phase was dried over MgSO4, fil-
tered, and concentrated under vacuum. The residue was purified
by flash column chromatography on silica gel eluting with a mix-
ture of PE/AcOEt (80:20) to give 3a (446 mg, 65%) as a yellow oil.
½
a 2D0
ꢁ
¼ þ8:6 (c 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): d 7.67 (dd,
J = 7.9, 1.3 Hz, 1H), 7.60 (1H, dd, J = 7.8, 1.6 Hz), 7.45 (1H, dt,
J = 7.8, 1.3 Hz), 7.23 (1H, dt, J = 7.5, 1.3 Hz), 5.92 (1H, m), 5.24
(2H, m), 4.08 (1H, dd, J = 8.2, 4.7 Hz), 2.63 (2H, m), 2.40 (3H, s),
1.73 (1H, br s); 13C NMR (62.5 MHz, CDCl3): d 142.4, 135.5, 133.3,
128.7, 128.5, 128.0, 124.7, 118.3, 62.8, 41.6, 34.8; HRMS-ESI: m/z
[M+H]+ calcd for C11H15NBr: 240.0388; found: 240.0384.
OTBDMS protected 1b0 (4.37 g, 75%) as
a pale yellow oil.
½
a 2D0
ꢁ
¼ þ15:5 (c 1, CH2Cl2); 1H NMR (250 MHz, CDCl3): d 8.42
(1H, d, J = 4.1 Hz), 7.42 (1H, td, J = 7.7, 1.5 Hz), 7.21–7.09 (6H, m),
6.97 (1H, m), 5.68 (1H, m), 5.07 (1H, d, J = 17.2 Hz), 5.02 (1H, d,
J = 10.2 Hz), 3.84 (2H, m), 3.72–3.58 (2H, m), 2.71 (1H, br s), 2.56
(2H, t, J = 6.4 Hz); 13C NMR (62.5 MHz, CDCl3): d 163.4, 148.6,
141.2, 135.7, 134.8, 127.85, 127.80, 126.9, 122.0, 121.3, 117.8,
67.7, 63.5, 61.7, 40.1, 25.8, 18.2, ꢂ5.45, ꢂ5.50; HRMS-ESI: m/z
[M+H]+ calcd for C17H21N2O: 269.1654; found: 269.1649. To a solu-
tion of 1b0 (4.26 g, 11.1 mmol) in THF (30 mL) was added TBAFꢀH2O
(5.19 g, 16 mmol) and the resulting mixture was stirred overnight
at rt. The solvent was removed under reduced pressure and the
residue was purified by flash column chromatography on silica
gel eluting with a mixture of PE/AcOEt (50:50) to give 1b (2.65 g,
4.1.6. (R)-(2-Bromophenyl)-1-methylpyrrolidine 4a
To a solution of 3a (415 mg, 1.7 mmol) in CH2Cl2 (5 mL) was
added Cp2Zr(H)Cl (580 mg, 2.2 mmol) in one portion at rt until
complete dissolution (ca 1 h). Next, Et3N (0.3 mL, 1.2 mmol) and
I2 (431 mg, 1.7 mmol) were added and the resulting mixture was
stirred for 1 h. Then CH2Cl2 (10 mL) and HCl (1 M, 5 mL) were
added. The organic phase was washed with HCl (1 M, 5 mL), a sat-
urated aqueous solution of Na2CO3 (5 mL), dried over MgSO4,
filtered, and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel eluting with a mixture of PE/
88%) as a pale yellow oil. ½a D20
ꢁ
¼ ꢂ10:0 (c 1, CH2Cl2); 1H NMR
AcOEt (95:5) to give compound 2a (300 mg, 72%). ½a D20
¼ þ89:8 (c
ꢁ
(250 MHz, CDCl3): d 8.37 (1H, d, J = 4.4 Hz), 7.50 (1H, td, J = 7.9,
1.7 Hz), 7.10 (5H, m), 7.06 (2H, m), 5.71 (1H, ddt, J = 17.1, 10.0,
7.0 Hz), 5.00–5.08 (2H, m), 3.86–3.78 (2H, m), 3.74 (1H, dd,
J = 10.6, 5.5 Hz), 3.58 (1H, dd, J = 10.6, 7.6 Hz), 2.93 (1H, br s),
2.56 (2H, m); 13C NMR (62.5 MHz, CDCl3): d 162.4, 149.0, 141.0,
136.1, 134.8, 128.3, 127.4, 127.2, 122.3, 121.8, 117.6, 66.1, 62.8,
61.3, 40.5; HRMS-ESI: m/z [M+H]+ calcd for C17H21N2O:
269.1654; found: 269.1649.
1, CH2Cl2). 1H NMR (250 MHz, CDCl3): d 7.59 (1H, dd, J = 7.8,
1.6 Hz), 7.50 (1H, dd, J = 7.8, 1.6 Hz), 7.31 (1H, t, J = 7.5 Hz), 7.08
(1H, t, J = 7.6 Hz), 3.55 (1H, t, J = 8.3 Hz), 3.25 (1H, t, J = 8.2 Hz),
2.39 (2H, m), 2.22 (3H, s), 1.87 (2H, m), 1.53 (1H, m); 13C NMR
(CDCl3, 62.5 MHz): d 142.2, 132.9, 128.6, 128.4, 128.1, 123.6,
69.7, 57.3, 41.1, 33.9, 23.1; HRMS-ESI: m/z [M+H]+ calcd for
C11H15Br: 240.0388; found: 240.0385.
4.1.7. (R)-1-Methyl-(2-diphenylphosphinophenyl)pyrrolidine L1
To a solution of 4a (140 mg, 0.6 mmol) in Et2O (5 mL) was
added n-BuLi (2.5 M in hexanes, 0.5 mL, 1.25 mmol) at 0 °C. The
resulting mixture was stirred for 2 h at rt, then a solution of PPh2Cl
(0.24 mL, 1.3 mmol) in Et2O (2 mL) was added. The reaction mix-
ture was stirred for 4 h at rt. The reaction was quenched with a sat-
urated aqueous solution of NaHCO3 (5 mL). The aqueous layer was
extracted with Et2O (2 ꢃ 5 mL). The organic phases were com-
bined, dried over MgSO4, filtered, and concentrated under vacuum.
The residue was purified by flash column chromatography on silica
gel eluting with a mixture of PE/AcOEt (95:5) to give L1 (135 mg,
4.1.4. (R)-tert-Butyl 2-(2-bromophenyl)-but-3-enylcarbamate 2a
To a solution of 1a (1.56 g, 4.5 mmol) in a mixture of CH2Cl2/
MeOH (1:1, 50 mL) was added in one portion Pb(OAc)4 (2.18 g,
4.9 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for
30 min, then NH4OHꢀHCl (3.2 g, 45 mmol) was added and the stir-
ring was continued for 30 min at 0 °C, after which the solvent was
removed under reduced pressure. The residue was taken up with
CH2Cl2 (50 mL) and the solid was filtered off. To the filtrate were
added Et3N (1.25 mL) and Boc2O (1.07 g, 4.9 mmol) and the result-
ing mixture was stirred at rt for 2 h. Next, H2O (20 mL) was added,
and the organic layer was washed with HCl (1 M, 10 mL), then
Na2CO3 (10%, 10 mL) dried over MgSO4, filtered, and the solvent
was removed under reduced pressure. The residue was purified
by flash chromatography on silica gel eluting with a mixture of
PE/CH2Cl2 (1:1) to give the compound 2a (880 mg, 60%) as a white
65%) as a white solid. ½a D20
ꢁ
¼ þ26:3 (c 1, CH2Cl2). 1H NMR
(250 MHz, CDCl3): d 7.59 (1H, ddd, J = 7.7, 4.2, 1.3 Hz), 7.30–7.13
(11H, m), 7.02 (1H, td, J = 7.5, 1.2 Hz), 6.65 (1H, ddd J = 7.7, 4.3,
1.2 Hz), 3.84 (1H, q, J = 7.8 Hz), 3.08 (1H, td, J = 8.4, 1.6 Hz), 2.13
(1H, m), 1.96 (3H, s), 1.80 (2H, m), 1.60 (1H, m), 1.42 (1H, m);
13C NMR (62.5 MHz, CDCl3): d 148.7 (d, J = 21.6 Hz), 137.8 (d,
J = 11.1 Hz), 137.5 (d, J = 10.3 Hz), 136.1 (d, J = 13.6 Hz), 134.7,
134.5, 134.4, 134.2, 133.6, 129.9, 129.1, 129.0, 128.9, 127.2, 68.4
(d, J = 23.5 Hz), 57.2, 40.7, 35.3, 23.2; 31P{1H} (101.2 MHz, CDCl3):
d ꢂ15.9; HRMS-ESI: m/z [M+H]+ calcd for C23H25NP: 346.1725;
found: 346.1717.
solid. Mp 97 °C. ½a D20
ꢁ
¼ þ5:7 (c 1, CH2Cl2); 1H NMR (250 MHz,
CDCl3): d 7.52 (1H, d, J = 8.0 Hz), 7.27 (2H, m), 7.09 (1H, m), 5.70
(1H, m), 5.17–5.10 (4H, m), 2.54 (1H, m), 2.43 (1H, m), 1.41 (9H,
s); 13C NMR (62.5 MHz, CDCl3): d 154.9, 141.4, 133.5, 133.1,
128.4, 127.3, 127.1, 122.6, 118.5, 79.6, 53.4, 39.5, 28.2.
4.1.5. (R)-1-(2-Bromophenyl)-N-methylbut-3-en-1-amine 3a
To a suspension of NaH (192 mg, 8 mmol) in DMF (6 mL) was
added a solution of 2a (934 mg, 2.86 mmol) in DMF (2 mL) at
0 °C. After 1 h of stirring, MeI (0.37 mL, 5.4 mmol) was added and
the resulting mixture was stirred overnight at rt. Water (10 mL)
and AcOEt (15 mL) were added. The aqueous layer was extracted
with AcOEt (2 ꢃ 15 mL). The organic phases were combined,
washed with H2O (5 ꢃ 5 mL), dried over MgSO4, filtered and con-
centrated under vacuum. The residue (762 mg, 2.2 mmol) was di-
luted into CH2Cl2 (22 mL), then TFA (2.2 mL) was added slowly at
0 °C. After 4 h of stirring at rt, the solvent, and the excess of TFA
were removed under reduced pressure. The residue was diluted
into CH2Cl2 (25 mL) and washed with a saturated aqueous solution
4.1.8. (R)-1-(Pyridin-2-yl)but-3-enamine 2b
To a solution of homoallylic amine 1b (2.61 g, 9.7 mmol) in a
mixture of CH2Cl2/MeOH (1:1, 70 mL) was added in one portion
Pb(OAc)4 (5.00 g, 4.9 mmol) at 0 °C. The resulting mixture was stir-
red at 0 °C for 30 min, then NH4OHꢀHCl (6.75 g, 97 mmol) was
added, and the stirring was continued for 30 min at 0 °C, after
which the solvent was removed under reduced pressure. The resi-
due was taken up with CH2Cl2 (50 mL), and the solid was filtered
off. The filtrate was washed with Na2CO3 (10%, 10 mL), dried over
MgSO4, filtered, and concentrated under vacuum. The residue
was purified by flash column chromatography on silica gel eluting
with a mixture of AcOEt/MeOH (9:1) to give 2b (1.28 g, 90%) as a

P.-O. Delaye et al. / Tetrahedron: Asymmetry 21 (2010) 2505–2511
2509
yellow oil. ½a 2D0
ꢁ
¼ þ47:3 (c 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): d
dissolution. Then Et3N (0.68 mL, 4.9 mmol) and I2 (1.14 g,
4.5 mmol) were added and the reaction mixture was stirred for
2 h. Next, CH2Cl2 (10 mL) was added and the organic phase was
washed with HCl (1 M, 2 ꢃ 3 mL), Na2CO3 (10%, 2 ꢃ 3 mL) dried
over MgSO4, filtered, and the solvent was removed under reduced
pressure. The residue was purified by flash chromatography on sil-
ica gel eluting with a mixture of PE/AcOEt (80:20) to give 2c (1.4 g,
8.56 (1H, d, J = 6.2 Hz), 7.64 (1H, td, J = 7.8, 1.7 Hz), 7.14 (1H, dd,
J = 6.2, 4.9 Hz), 5.77 (1H, dddd, J = 18.5, 10.7, 7.8, 6.6 Hz), 5.10
(1H, d, J = 18.5 Hz), 5.08 (1H, d, J = 10.7 Hz), 4.04 (1H, dd, J = 7.9,
5.3 Hz), 2.59 (1H, dt, J = 13.7, 6.4 Hz), 2.39 (1H, dt, J = 13.7,
7.9 Hz), 1.81 (2H, br s); 13C NMR (62.5 MHz, CDCl3): d 163.9,
148.9, 136.2, 135.0, 121.7, 120.7, 117.6, 56.3, 43.1; HRMS-ESI: m/
z [M+H]+ calcd for C9H13N2: 149.1079; found: 149.1082.
83%) as a red oil. ½a D20
ꢁ
¼ þ14:0 (c 1, CH2Cl2); 1H NMR (250 MHz,
CDCl3): d 1.75 (2H, m), 2.20 (2H, q, J = 6.9 Hz), 2.50 (1H, br s),
2.68 (2H, t, J = 6.8 Hz), 3.60–3.65 (3H, m), 3.74 (1H, t, J = 6.1 Hz),
3.96–4.12 (9H, m), 7.05–7.25 (5H, m); 13C NMR (62.5 MHz, CDCl3):
d 23.0, 33.0, 50.6, 57.9, 62.7, 64.8, 66.7, 66.8, 68.2, 68.4, 69.4, 89.8,
127.2, 128.0, 128.7, 139.2; HRMS-ESI: m/z [M+H]+ calcd for
C22H26NOFe: 376.1364; found: 376.1358.
4.1.9. 2-[(R)-Pyrrolidin-2-yl]pyridine 3b
To a solution of 2b (1.28 g, 8.6 mmol) and Et3N (1.3 mL) in
CH2Cl2 (20 mL) was added TrCl (2.4 g, 8.6 mmol). The reaction mix-
ture was stirred for 12 h at rt. Water (5 mL) was added and the or-
ganic layer was washed with NaHCO3 (10%, 5 mL), dried over
MgSO4, and concentrated under vacuum to give the protected
amine which was used in the next step without purification. To a
solution of the crude amine (3.36 g, 8.6 mmol) in CH2Cl2 (30 mL)
was added Cp2Zr(H)Cl (2.45 g, 9.5 mmol) in two portions and the
reaction mixture was stirred until complete dissolution (ca 1 h).
Next, Et3N (1.35 mL) and I2 (2.18 g, 8.6 mmol) were successively
added and the stirring was continued for 4 h. Water (10 mL) was
added and the heterogeneous mixture was vigorously stirred for
1 h. The organic phase was extracted with water (3 ꢃ 10 mL). The
aqueous phases were combined and concentrated to 10 mL,
saturated with Na2SO4, then extracted with CH2Cl2 (4 ꢃ 20 mL).
The organic extracts were combined, dried over Na2SO4, filtered,
and concentrated under vacuum to give 3b (0.89 g, 69%).
4.1.12. (2R)-Pyrrolidin-2-ylferrocene 3c
A mixture of 2c (2.96 g, 7.89 mmol) and Pd(OH)2/C (20%,
500 mg) in MeOH (80 mL) was stirred under an atmosphere of H2
at rt for 8 h. The reaction mixture was filtered through a pad of Cel-
ite and concentrated under vacuum. The residue was purified by
flash chromatography on silica gel eluting with a gradient of
AcOEt?AcOEt/Et2NH (98:2) to give 3c as a red oil (1.9 g, 99%).
½
a 2D0
ꢁ
¼ þ28:5 (c 1, CH2Cl2); 1H NMR (CDCl3, 250 MHz): d 1.69–
2.00 (3H, m), 2.09–2.26 (1H, m), 2.77–2.95 (1H, m), 3.04–3.21
(1H, m), 3.84 (1H, t, J = 7.3 Hz), 4.10–4.26 (9H, m); 13C NMR
(62.5 MHz, CDCl3): d 23.5, 30.9, 44.5, 57.4, 66.9, 67.2, 67.3, 67.4,
67.6, 80.0; HRMS-ESI: m/z [M+H]+ calcd for C14H18NFe: 256.0723;
found: 256.0720.
½
a 2D0
ꢁ
¼ þ78:4 (c 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): d 8.52 (1H,
d, J = 4.2 Hz), 7.64 (1H, td, J = 7.8, 1.6 Hz), 7.34 (1H, d, J = 7.8 Hz),
7.15 (1H, dd, J = 6.7, 6.2 Hz), 4.30 (1H, t, J = 7.1 Hz), 3.70 (1H, br
s), 3.20 (1H, dt, J = 10.5, 6.5 Hz), 3.02 (1H, dt, J = 10.5, 7.2 Hz),
2.25 (1H, m), 1.93–1.73 (3H, m); 13C NMR (62.5 MHz, CDCl3): d
162.2, 148.9, 136.5, 122.0, 121.5, 63.2, 47.0, 33.7, 25.8.
4.1.13. (R)-1-[2-(Diphenylphosphino)benzyl-2-ferrocenylpyr-
rolidine L4
To a solution of 3c (375 mg, 1.7 mmol) and 2-diphenylphospho-
nobenzaldehyde (485 mg, 1.67 mmol) in DCE (10 mL) was added
NaBH(OAc)3 (550 mg, 2.64 mmol). After 18 h of stirring, a satu-
rated aqueous solution of NaHCO3 (10 mL) was added. The aqueous
layer was extracted with CH2Cl2 (2 ꢃ 5 mL). The organic phases
were combined, dried over MgSO4, filtered, and concentrated un-
der vacuum. The residue was purified by flash column chromatog-
raphy on silica gel eluting with a mixture of PE/AcOEt (95:5) to
½
a 2D0
ꢁ
¼ þ78 (c 1, CH2Cl2). HRMS-ESI: m/z [M+H]+ calcd for
C9H13N2: 149.1079; found: 149.1080.
4.1.10. 2-[(R)-1-(Diphenylphosphinoborane)pyrrolidin-2-
yl]pyridine L2ꢀBH3
To a solution of 3b (0.88 g, 5.9 mmol) and Et3N (0.89 ml,
6.5 mmol) in THF (20 mL) was added PPh2Cl (1.13 mL, 5.9 mmol)
at 0 °C and the resulting solution was stirred for 4 h at rt. The solid
was filtered off under Ar. To the filtrate was added a solution of
BH3ꢀSMe2 (2 M in THF, 3 mL, 6 mmol) and the reaction mixture
was stirred for 2 h at rt, after which water (10 mL) was added.
The organic layer was dried over MgSO4, filtered, and the solvent
was removed under reduced pressure. The crude material was di-
luted into CH2Cl2 (20 mL), then DABCO (662 mg, 5.9 mmol) was
added. The solution was stirred overnight at rt. The solvent was re-
moved under vacuum and the residue was purified by flash column
chromatography on silica gel eluting with a mixture of PE/AE (9:1)
give L4 (628 mg, 71%) as a yellow foam. ½a D20
¼ þ81:1 (c 1, CH2Cl2).
ꢁ
1H NMR (250 MHz, CDCl3): d 1.89 (2H, m), 2.11 (3H, app q,
J = 8.1 Hz), 2.58 (1H, td, J = 8.3, 4.6 Hz), 3.36 (1H, t, J = 7.1 Hz),
3.62 (1H, dd, J = 13.4, 2.6 Hz), 3.74 (1H, d, J = 13.6 Hz), 4.01–4.10
(9H, m), 6.81 (1H, dd, J = 6.8, 4.2 Hz), 7.09 (1H, t, J = 7.3 Hz),
7.18–7.31 (12H, m), 7.38 (1H, m); 13C NMR (62.5 MHz, CDCl3): d
22.4, 31.8, 52.4, 55.8 (d, J = 18.5 Hz), 62.6, 66.4, 67.0, 67.9, 68.3,
69.8, 88.7, 126.6 (2C), 128.5 (2C), 128.7 (d, J = 5.3 Hz), 133.65 (d,
J = 19.8 Hz), 133.70 (d, J = 19.8 Hz), 134.0 (2C), 134.2, 135.8 (d,
J = 14.7 Hz), 137.7 (d, J = 10.5 Hz), 137.9 (d, J = 10.5 Hz), 145.0 (d,
J = 22.8 Hz); 31P{1H} (101.2 MHz, CDCl3): d ꢂ15.5; HRMS-ESI: m/z
[M+H]+ calcd for C33H33FeNP: 530.1700; found: 530.1696.
to give L2ꢀBH3. (1.27 g, 62%) as
a white solid. Mp 82 °C;
½
a 2D0
ꢁ
¼ þ81:0 (c 1, CH2Cl2). 1H NMR (250 MHz, CDCl3): d 0.16–
1.60 (3H, br m), 1.90 (2H, m), 2.06 (1H, m), 2.39 (1H, dq, J = 11.3,
8.4 Hz), 3.37 (1H, m), 3.52 (1H, m), 5.07 (1H, ddd, J = 8.6, 6.2,
2.3 Hz), 7.01 (1H, dd, J = 6.8, 5.4 Hz), 7.09 (1H, d, J = 7.8 Hz), 7.29–
7.68 (11H, m), 8.42 (1H, d, J = 4.1 Hz); 13C NMR (62.5 MHz, CDCl3):
d 24.7 (d, J = 5.3 Hz), 34.8 (d, J = 5.2 Hz), 49.3, 64.9 (d, J = 4.6 Hz),
132.0 (d, J = 10.3 Hz), 128.1 (d, J = 9.8 Hz), 128.3 (d, J = 9.5 Hz),
129.1 (d, J = 23.2 Hz), 130.9, 132.3 (d, J = 10.4 Hz), 135.8, 148.6,
163.8; 31P NMR {1H} (101.2 MHz, CDCl3): d 56.4; HRMS-ESI: m/z
[M+Na]+ calcd for C21H24BN2PNa: 369.1668; found: 369.1663.
4.1.14. N-Methyl-(2R)-pyrrolidin-2-ylferrocene 4c
To a solution of 3c (538 mg, 2.1 mmol) in MeOH (10 mL) was
added formaldehyde (37% in water, 4.7 mL, 63 mmol). The result-
ing mixture was stirred for 30 min, then NaBH4 (800 mg, 21 mmol)
was added in small portions at 0 °C, and the stirring was continued
for 3 h at rt. Next, CH2Cl2 (40 mL) was added after which H2O
(10 mL) was successively added. The organic phase was dried over
Na2SO4, filtered, and concentrated under vacuum. The residue was
purified by flash column chromatography on silica gel eluting with
AcOEt to give 4c (519 mg, 92%) as a red oil. ½a D20
¼ þ89:2 (c 1,
ꢁ
4.1.11. (R)-2-Phenyl-2-[(R)-2-ferrocenylpyrrolidin-1-yl]ethanol 2c
To a solution of 1c (1.67 g, 4.5 mmol) in CH2Cl2 (15 mL) under
an atmosphere of argon, was added Cp2Zr(H)Cl (2.42 g, 9.38 mmol)
in one portion and the resulting mixture was stirred until complete
CH2Cl2); 1H NMR (250 MHz, CDCl3): d 1.69–1.98 (2H, m), 1.98–
2.13 (1H, m), 2.17 (3H, s), 2.19–2.34 (2H, m), 2.89 (1H, t,
J = 8.1 Hz), 3.03–3.14 (1H, m), 4.02–4.26 (9H, m); 13C NMR
(62.5 MHz, CDCl3): d 88.4, 70.2, 68.82, 68.79, 67.7, 66.2, 65.9,

2510
P.-O. Delaye et al. / Tetrahedron: Asymmetry 21 (2010) 2505–2511
57.9, 40.4, 32.5, 22.8; HRMS-ESI: m/z [M+H]+ calcd for C22H26NOFe:
270.0951; found: 270.0942.
4.2.5. 2-[(2R)-N-Methylpyrrolidin-20-yl]-(1pS)-diphenylphosphi-
noferrocene L7
To a solution of 5c (121 mg, 0.35 mmol) in Et2O (1.3 mL) was
added dropwise sec-butyllithium (1.3 M in hexanes, 0.48 mL) at
ꢂ78 °C under Ar. The reaction mixture was stirred for 3h at
4.2. General method for functionalisation of 4c
To a solution of 4c (269 mg, 1 mmol) in Et2O (3 mL) was added
dropwise sec-butyllithium (1.3 M in hexanes, 1.15 mL) at ꢂ78 °C
under Ar. The reaction mixture was stirred for 3 h at ꢂ78 °C, then
1 h at 0 °C. The electrophilic reagent was added (1.5 mmol) and the
stirring was maintained for 1 h at rt before adding a saturated
aqueous solution of NaHCO3 (3 mL). The aqueous layer was ex-
tracted with Et2O (2 ꢃ 3 mL), and the organic phases were com-
bined, dried over Na2SO4 filtered, and concentrated under
vacuum. The residue was purified by flash column chromatogra-
phy on silica gel eluting with a mixture of PE/AcOEt.
ꢂ78 °C, then 1h at 0 °C. PPh2Cl (100
lL, 0.52 mmol) was added
and the stirring was maintained for 1h at rt before adding a satu-
rated aqueous solution of NaHCO3 (3 mL). The aqueous layer was
extracted with Et2O (2 ꢃ 3 mL), the organic phases were combined,
dried over Na2SO4, filtered and concentrated under vacuum. The
residue was purified by flash column chromatography on silica
gel eluting with a mixture of PE/Et2O (98:2) to give 2-[(2R)-N-
Methylpyrrolidin-20-yl]-3-trimethylsilyl-(1pS)-diphenylphosphi-
noferrocene (89 mg, 82%) to which was added TBAF (1M IN THF, 4
mL). The resulting mixture was heated to reflux for 3 days. Water
(4 mL) was then added. The aqueous layer was extracted with
AcOEt (2 ꢃ 4 mL), and the organic phases were combined, washed
with 6 mL of brine, dried over Na2SO4, filtered and concentrated
under vacuum. The residue was purified by flash column chroma-
tography on silica gel using a mixture of AcOEt/Et2NH (98:2) to
4.2.1. 2-[(2R)-N-Methylpyrrolidin-2-yl]-(1pR)-
phenylthiolferrocene L4
Yield = 71%, yellow oil; ½a D20
ꢁ
þ 211:9 (c 1, CH2Cl2); 1H NMR
(250 MHz, CDCl3): d 1.14–1.35 (1H, m), 1.40–1.74 (2H, m), 1.76–
1.95 (1H, m), 2.24 (1H, dd, J = 17.7, 9.2 Hz), 2.66 (3H, s), 3.03–
3.15 (1H, m), 3.28 (1H, t, J = 8.2 Hz), 4.21 (5H, s), 4.32 (1H, t,
J = 2.4 Hz), 4.40–4.47 (2H, m), 6.97–7.19 (5H, m); 13C NMR (CDCl3,
62.5 MHz): d 22.1, 34.9, 42.4, 57.9, 64.2, 67.6, 67.9, 70.3, 72.0, 75.7,
94.9, 124.4, 125.3, 128.3,140.8; HRMS-ESI: m/z [M+H]+ calcd for
give L7 (34 mg, 44%) as a red oil. ½a D20
¼ ꢂ339:0 (c 0.6, CH2Cl2);
ꢁ
1H NMR (250 MHz, CDCl3): d 1.78–2.01 (2H, m), 2.20 (2H, m),
2.34–2.54 (1H, m), 2.97–3.17 (1H, m), 3.36 (1H, dt, J = 8.3,
3.5 Hz), 3.92 (5H, s), 4.00 (1H, m), 4.40 (1H, t, J = 2.3 Hz), 4.57
(1H, m), 7.18–7.42 (8H, m), 7.56–7.67 (2H, m); 13C NMR
(62.5 MHz, CDCl3): d 22.5, 35.4, 40.3, 57.7, 63.2 (d, J = 10.0 Hz),
69.3 (d, J = 4.3 Hz), 69.4, 70.2, 70.8 (d, J = 4.6 Hz), 75.2 (d,
J = 9.1 Hz), 127.8, 127.9, 128.0, 129.0, 132.7 (d, J = 18.7 Hz), 135.2
(d, J = 22.1 Hz), 138.0 (d, J = 8.1 Hz), 139.8 (d, J = 8.3 Hz), 1C is miss-
ing; 31P NMR {1H} (101.2 MHz, CDCl3): d ꢂ25.9; HRMS-ESI: m/z
[M+H]+ calcd for C27H29NPFe: 454.1387; found: 454.139.
C21H24FeNS: 378.0979; found: 378.0980.
4.2.2. 2-[(2R)-N-Methylpyrrolidin-2-yl]-(1pR)-diethylphosphite-
ferrocene L5
Yield = 62%, yellow oil; ½a D20
ꢁ
¼ þ222:3 (c 1, CH2Cl2); 1H NMR
(250 MHz, CDCl3): d 1.14 (3H, t, J = 7.0 Hz), 1.38 (3H, t, J = 7.0 Hz),
1.49–1.88 (3H, m), 2.10–2.36 (2H, m), 2.57 (3H, s), 3.14 (1H, t,
J = 7.6 Hz), 3.25 (1H, t, J = 8.0 Hz), 3.44–3.61 (1H, m), 3.69–3.87
(1H, m), 3.96–4.11 (2H, m), 4.18 (5H, s), 4.29 (1H, t, J = 2.3 Hz),
4.37 (1H, m), 4.49 (1H, m); 13C NMR (62.5 MHz, CDCl3): d 17.2
(d, J = 3.5 Hz), 17.9 (d, J = 6.6 Hz), 22.6, 36.8 (d, J = 4.7 Hz), 42.5,
58.5, 59.8, 64.5 (d, J = 21.9 Hz), 64.8 (d, J = 5.0 Hz), 68.4, 69.5 (d,
J = 4.3 Hz), 69.9 (2C), 75.5 (d, J = 20.9 Hz), 96.4 (d, J = 22.4 Hz); 31P
NMR {1H} (101.2 MHz, CDCl3): d 155.4; HRMS-ESI: m/z [M+H]+
calcd for C19H28FeNO2P: 390.1285; found: 390.1290.
Acknowledgments
Financial support of this work by CNRS and the Ministère de
l’Enseignement Supérieur et de la Recherche is gratefully
acknowledged.
References
1. Catalytic Asymmetric Synthesis; Ojima, I., Ed., 3rd ed.; Wiley-VCH: New York,
2010.
4.2.3. 2-[(2R)-N-Methylpyrrolidin-2-yl]-(1pR)-diphenylpho-
sphinoferrocene L6
2. (a) Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett. 1974, 15, 4405–
4408; (b) Hayashi, T.; Tajika, M.; Tamao, K.; Kumada, M. J. Am. Chem. Soc. 1976,
98, 3718–3719; (c) Matt, P. V.; Pfaltz, A. Angew. Chem., Int. Ed. 1993, 32, 566–
568; (d) Matt, P. V.; Loiseleur, O.; Koch, G.; Pfaltz, A.; Lefeber, C.; Feucht, T.;
Helmchen, G. Tetrahedron: Asymmetry 1994, 5, 573–584; (e) Matt, P. V.; Lloyd-
Jones, G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder, M.;
Rüegger, H.; Pregosin, P. S. Helv. Chim. Acta 1995, 78, 265–284; (f) Sprinz, J.;
Helmchen, G. Tetrahedron Lett. 1993, 34, 1769–1772; (g) Sprinz, J.; Kiefer, M.;
Helmchen, G.; Reggelin, M.; Huttner, G.; Walter, O.; Zsolnai, L. Tetrahedron Lett.
1994, 35, 1523–1526; (h) Fache, F.; Schultz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159–2231; (i) McCarthy, M.; Guiry, P. J. Tetrahedron
2001, 57, 3809–3844; (j) Vasse, J.-L.; Stranne, R.; Zalubovskis, R.; Gayet, C.;
Moberg, C. J. Org. Chem. 2003, 68, 3258–3270.
Yield = 67%, yellow solid, mp 108–112 °C; ½a D20
¼ þ255:5 (c 1,
ꢁ
CH2Cl2); 1H NMR (250 MHz, CDCl3): d 1.48–1.83 (4H, m), 2.22
(1H, q, J = 8.1 Hz), 2.51 (3H, s), 3.03 (1H, t, J = 7.6 Hz), 3.30 (1H, t,
J = 7.7 Hz), 3.89 (1H, s), 3.96 (5H, s), 4.30 (1H, s), 4.46 (1H, s),
7.18–7.22 (5H, m), 7.37 (3H, m), 7.57 (2H, m); 13C NMR
(62.5 MHz, CDCl3): d 22.4, 36.0 (d, J = 6.0 Hz), 42.2, 58.0, 64.7 (d,
J = 5.2 Hz), 68.5, 69.5 (d, J = 8.9 Hz), 69.6 (2C), 71.2 (d, J = 4.7 Hz),
97.5 (d, J = 22.9 Hz), 127.6 (d, J = 8.2 Hz), 127.7, 127.9 (d,
J = 7.9 Hz), 129.0, 132.5 (d, J = 18.2 Hz), 135.3 (d, J = 21.7 Hz),
138.1 (d, J = 8.5 Hz), 140.5 (d, J = 8.5 Hz); 31P NMR {1H}
(101.2 MHz, CDCl3): d ꢂ23.5; HRMS-ESI: m/z [M+H]+ calcd for
3. (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336–345; (b) Guiry, P. J.;
Saunders, C. P. Adv. Synth. Catal. 2004, 346, 497–537; (c) Togni, A.; Burckhardt,
U.; Gramlich, V.; Pregosin, P. S.; Salzmann, R. J. Am. Chem. Soc. 1996, 118, 1031–
1037.
C27H29NPFe: 454.1387; found: 454.1386.
4. (a) Hiroi, K.; Suzuki, Y. Heterocycles 1999, 50, 89; (b) Hiroi, K.; Suzuki, Y.; Abe, I.
Tetrahedron: Asymmetry 1999, 10, 1173–1188; (c) Mino, T.; Tanaka, Y. I.;
Sakamoto, M.; Fujita, T. Heterocycles 2000, 53, 1485; (d) Mino, T.; Tanaka, Y. I.;
Akita, K.; Anada, K.; Sakamoto, M.; Fujita, T. Tetrahedron: Asymmetry 2001, 12,
1677–1682; (e) Ganter, C.; Wagner, T. Chem. Ber. 1995, 128, 1157–1161; (f)
Gotov, B.; Schmaltz, H.-G. Org. Lett. 2001, 3, 1753–1756; (g) Farrell, A.;
Goddard, R.; Guiry, P. J. J. Org. Chem. 2002, 67, 4209.
5. Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Org. Lett. 2005, 7, 4887–4889.
6. Ahari, M.; Joosten, A.; Vasse, J.-L.; Szymoniak, J. Synthesis 2008, 61–68.
7. (a) Gomez Arrayas, R.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45,
7674–7715; (b) Colacot, T. J. Chem. Rev. 2003, 103, 3101–3118; (c) Hayashi, T.;
Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima, T.; Hamada, Y.; Matsumoto,
A.; Kawakami, S.; Konishi, M.; Yamamoto, K.; Kumada, M. Bull. Chem. Soc. Jpn.
1980, 53, 1138; (d) Hayashi, T.; Kumada, M. Acc. Chem. Res. 1982, 15, 395; (e)
4.2.4. 2-[(2R)-N-Methylpyrrolidin-2-yl]-(1pR)-trimethylsilylferrocene
5c
Prepared according to the above procedure. 83%, yellow oil;
½
a 2D0
ꢁ
¼ þ89:0 (c 0.4, CH2Cl2); 1H NMR (250 MHz, CDCl3): d 0.25
(9H, s), 1.29–1.49 (1H, m), 1.51–1.85 (2H, m), 1.98–2.15 (1H, m),
2.24 (1H, dd, J = 17.6, 9.3 Hz), 2.64 (3H, s), 2.99–3.20 (2H, m),
4.01 (1H, dd, J = 2.1, 1.3 Hz), 4.04–4.11 (5H, m), 4.25 (1H, t,
J = 2.2 Hz), 4.41 (1H, s); 13C NMR (62.5 MHz, CDCl3): d 0.7, 22.3,
36.8, 42.6, 58.2, 65.2, 67.8, 68.7, 68.8, 68.9, 73.7, 97.7; HRMS-ESI:
m/z [M+H]+ calcd for C18H28NFeSi: 342.1340; found: 342.1346.

P.-O. Delaye et al. / Tetrahedron: Asymmetry 21 (2010) 2505–2511
2511
Ohno, A.; Yamane, M.; Hayashi, T.; Oguni, N.; Hayashi, M. Tetrahedron:
Asymmetry 1995, 6, 2495.
14. (a) García Mancheño, O.; Priego, J.; Cabrera, S.; Gómez Arrayás, R.; Llamas, T.;
Carretero, J. C. J. Org. Chem. 2003, 68, 3679–3686; (b) Lam, F. L.; Au-Yeung, T. T.-
L.; Kwong, F. Y.; Zhou, Z.; Wong, K. Y.; Chan, A. S. C. Angew. Chem., Int. Ed. 2008,
47, 1280–1283.
15. (a) Geisler, F. M.; Helmchen, G. J. Org. Chem. 2006, 71, 2486–2492; (b) Hayashi,
T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima, T.; Hamada, Y.;
Matsumoto, A.; Kawakami, S.; Konishi, M.; Yamamoto, K.; Kumada, M. Bull.
Chem. Soc. Jpn. 1980, 53, 1138–1142; (c) Hayashi, T.; Kumada, M. Acc. Chem. Res.
1982, 15, 395–401; (d) Ohno, A.; Yamane, M.; Hayashi, T.; Oguni, N.; Hayashi,
M. Tetrahedron: Asymmetry 1995, 6, 2495–2502.
16. Ahern, T.; Müller-Bunz, H.; Guiry, P. J. J. Org. Chem. 2006, 71, 7596–7602.
17. Meanney, K. Ph.D. Dissertation, National University of Ireland, 2002.
18. (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395; (b) Zhan Lu, S. M.
Angew. Chem., Int. Ed. 2008, 47, 258–297; For reviews, see: (c) Pfaltz, A.;
Lautens, M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999; Vol. 2, (d) Trost, B. M.;
Lee, C. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York,
2000; pp 593–649; (e) Nishibayashi, Y.; Uemura, S. In Comprehensive
Organometallic Chemistry; Mingos, D. M. P., Crabtree, R. H., Eds.; Elsevier
Science: Amsterdam, The Netherlands, 2003; Vol. 11, pp 75–122; (f) Tsuji, J. In
Palladium Reagents and Catalysts; Wiley: Chichester, UK, 2004.
19. Steinhagen, H.; Reggelin, M.; Helmchen, G. Angew. Chem., Int. Ed. 1997, 36,
2108–2110.
8. (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207–2293; (b) Yanada, R.;
Negoro, N.; Okaniwa, M.; Ibuka, T. Tetrahedron 1999, 55, 13947–13956; (c)
Yanada, R.; Okaniwa, M.; Kaieda, A.; Ibuka, T.; Takemoto, Y. J. Org. Chem. 2001,
66, 1283–1286; (d) Yanada, R.; Kaieda, A.; Takemoto, Y. J. Org. Chem. 2001, 66,
7516–7518; (e) Fiorelli, C.; Savoia, D. J. Org. Chem. 2007, 72, 6022–6028; (f)
Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem. 1994, 59,
7766–7773; (g) Yanada, R.; Kaeida, A.; Akira, K.; Takemoto, Y. Heterocycles
2005, 66, 101–106; (h) Negoro, N.; Yanada, R.; Okaniwa, M.; Yanada, K.; Fujita,
T. Synlett 1998, 835–836; (i) Bhuyan, P. J.; Prajapati, D.; Sandhu, J. S. Tetrahedron
Lett. 1993, 34, 7975–7976; (j) Giammaruco, M.; Taddei, M.; Ulivi, P. Tetrahedron
Lett. 1993, 34, 3635–3638; (k) Tanaka, H.; Yamashita, S.; Ikemoto, Y.; Torii, S.
Chem. Lett. 1987, 673–674.
9. (a) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org.
Chem. 2005, 70, 3464–3471; (b) Agami, C.; Couty, F.; Evano, G. Tetrahedron:
Asymmetry 2000, 11, 4639–4643; (c) Wu, M.-J.; Pridgen, L. N. Synlett 1990, 636–
637.
10. Delaye, P.-O.; Pradhan, T. K.; Lambert, E.; Vasse, J.-L.; Szymoniak, J. Eur. J. Org.
Chem. 2010, 3395–3406.
11. For an alternative synthesis of ent-3b see: Chelucci, G.; Falorni, M.; Giacomelli,
G. Synthesis 1990, 1121–1122.
12. Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc.
1970, 92, 5389–5393.
13. (a) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.; Tijani, A. J. Am.
Chem. Soc. 1994, 116, 4062–4066; (b) Schwink, L.; Knochel, P. Chem. Eur. J.
1998, 4, 950–968.
20. Saitoh, A.; Achiwa, K.; Tanaka, K.; Morimoto, T. J. Org. Chem. 2000, 65, 4227–
4240.
21. Buchwald, S. L.; La Maire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S. M. Org.
Synth. 1993, 71, 77–81.