Studies on palladium-catalyzed enantioselective cyclization of 3,4-allenylic hydrazines with organic halides

Article abstract of DOI:10.1016/j.tet.2008.09.049

A convenient route to optically active pyrazolidine derivatives from Pd(0)/(R,R)-Bn-BOX-catalyzed enantioselective cyclization of 3,4-allenylic hydrazines in the presence of organic halides has been developed, the ee value is 75-84%. The absolute configuration of the products was determined by the conversion of one of the products to a known product prepared in this group. The reaction may proceed via the oxidative addition, intermolecular carbometallation of the allene moiety forming a π-allylic palladium intermediate, and the intramolecular enantioselective allylation.

Full text of DOI:10.1016/j.tet.2008.09.049

Tetrahedron 64 (2008) 11159–11166
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies on palladium-catalyzed enantioselective cyclization of 3,4-allenylic
hydrazines with organic halides
,
,
Wei Shu a, Qing Yang a b, Guochen Jia c, Shengming Ma a
*
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, PR China
b State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Jilin University, Changchun 130012, PR China
c Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient route to optically active pyrazolidine derivatives from Pd(0)/(R,R)-Bn-BOX-catalyzed
enantioselective cyclization of 3,4-allenylic hydrazines in the presence of organic halides has been
developed, the ee value is 75–84%. The absolute configuration of the products was determined by the
conversion of one of the products to a known product prepared in this group. The reaction may proceed
Received 25 July 2008
Received in revised form
17 September 2008
Accepted 19 September 2008
Available online 26 September 2008
via the oxidative addition, intermolecular carbometallation of the allene moiety forming a
palladium intermediate, and the intramolecular enantioselective allylation.
p-allylic
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Allenes
Hydrazine
Halides
Cyclization
Enantioselectivity
1. Introduction
means for forming new carbon–carbon,9 carbon–nitrogen,10 car-
bon–oxygen,11 and carbon–sulfur12 bonds in an enantioselective
manner. Most work in this area has been focused on the de-
velopment of improved chiral ligands for intermolecular nucle-
ophilic substitution of the allylic systems.13 In contrast, relatively
little work has been done with more complicated intramolecular
systems.14 Larock et al. reported a palladium-catalyzed asym-
metric hetero- and carboannulation of allenes using aryl and
vinylic iodides bearing a nucleophilic functionality to construct
various cyclic products in moderate to good ee.15 In 2004, our
group reported an efficient method for the synthesis of pyr-
azolidine derivatives through Cu- and Pd-catalyzed asymmetric
one-pot tandem addition–cyclization reaction of 2-(20,30-alka-
dienyl)-3-ketoesters and dibenzyl azodicarboxylate in the pres-
ence of organic halides in high ee (up to 99%) but moderate
diastereoselectivity (cis/trans¼33:77 to 45:55).16 Recently,
Pyrazolidine, an important heterocyclic unit existed in many
natural and bioactive products,1 has attracted more and more at-
tention of both bio- and synthetic chemists. Although the pyr-
azolidine structural unit is usually available from [3þ2]
cycloaddition2,3 and hetero-Diels–Alder cycloaddition of 1,3-
cyclopentadiene with diethyl azodicarboxylate,4 these existing
methods often suffer from the complexity of starting materials.
Since enantiomers often exhibit significant variance in biological
activities,5 the development of asymmetric synthetic methodolo-
gies has been of prime importance to organic chemists. However,
the catalytic asymmetric synthesis of pyrazolidine derivatives has
been much less explored.6
Transition metal-catalyzed coupling–cyclization reactions in-
volving functionalized allenes have been demonstrated to be one
of the most powerful protocols to construct carbo- and hetero-
cycles.7 We and others have developed transition metal-cataly-
zed coupling–cyclization reactions of functionalized allenes with
organic halides.8 Meanwhile, the palladium-catalyzed asymmet-
ric allylic substitution reaction has been shown to be a useful
a
highly diastereoselective palladium-catalyzed cyclization of
optically active 3,4-allenylic hydrazines with organic halides was
also realized in our group by using Pd(OAc)2 and (R,R)-Bn-BOX as
the ligand.17 However, the high enantiopurities of the products
in the above mentioned two methods came partially from the
preintroduced chiral information in the substrates. Herein, we
wish to report a catalytic enantioselective synthesis of pyr-
azolidine derivatives by cyclization of 3,4-allenylic hydrazines in
the presence of organic halides.
* Corresponding author.
E-mail address: masm@mail.sioc.ac.cn (S. Ma).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.049

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W. Shu et al. / Tetrahedron 64 (2008) 11159–11166
Table 2
2. Results and discussion
Ligand effect on the Pd-catalyzed enantioselective coupling–cyclization of 1b
with PhIa
2.1. Synthesis of starting 3,4-allenylic hydrazines
Ph
C
CO2Bn
CO2Bn
5 mol% Pd(dba)2
10 mol% ligand
HN
N
CO2Bn
The starting 3,4-allenylic hydrazines were synthesized via Cu-
catalyzed Michael addition of 2-(20,30-butadienyl)malonate with
azodicarboxylate (Scheme 1).
N
+
PhI
N
0.45 equiv Ag3PO4
THF, 70 °C
CO2Bn
CO2Bn
CO2Bn
BnO2C
1b
BnO2
2a
3ba
CO2R2
10 mol% Cu(OTf)2
R2O2C
HN
CO2R1
CO2R1
10 mol% Ph-BOX
N
N
CO2R2
CO2R1
Entry
Ligand
Yield of
eec (%)
N
3aa (%)b
+
DCM, rt
CO2R2
R1O2C
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
75
83
d
d
80
83
d
Complex
NRd
75
1a: R1 = Me, R2 = Bn, 88%
1b: R1 = Bn, R2 = Bn, 77%
1c: R1 = Et, R2 = Et, 85%
1d: R1 = Et, R2 = Bn, 54%
69
NRd
Scheme 1. Synthesis of 3,4-allenylic hydrazines 1a–1d.
a
The reaction was carried out using 0.1 mmol of 1b, 0.12 mmol of PhI, 0.045 mmol
of Ag3PO4, 5 mol % of Pd(dba)2, and 10 mol % of ligand in 2 mL of THF at 70 ꢀC in
a Schlenk tube with a screw cap.
2.2. Pd(0)-catalyzed enantioselective cyclization of 3,4-
allenylic hydrazines with organic halides
b
Isolated yields.
The ee values were determined by chiral HPLC analysis.
NR¼No reaction.
c
d
Our initial efforts were focused on the cyclization of 3,4-allenylic
hydrazine 1a with iodobenzene. The effect of solvents and the
amount of silver salt were screened with Ag3PO4 being used as
the base (Table 1). THF was found to be the best solvent in terms of
the enantioselectivity (compare entries 1–5, Table 1). No remark-
able change of ee of the product was observed by increasing the
amount of Ag3PO4 from 0.4 to 0.5 equiv, although the use of
0.45 equiv of Ag3PO4 afforded the product 3aa in the highest yield
(entries 5–7, Table 1). Lowering the reaction temperature to 70 ꢀC
further improved the yield and the enantioselectivity (compare
entries 7 and 8, Table 1).
However, because it is quite difficult to prepare pure 1a, allenylic
hydrazine with dibenzyl malonate moiety 1b was used instead to
screen the ligands for the reaction (Table 2). As shown in Table 2,
the reaction in THF at 70 ꢀC with 0.45 equiv of Ag3PO4 as the base
afforded the desired product 3ba in good enantiomeric excess
(83%) when bisoxazoline (R,R)-L1 and Pd(dba)2 were used as the
catalysts (entry 1, Table 2). Notably, the trioxazoline ligands L4 and
O
O
O
O
N
N
N
PPh2 N
N
O
Bn
Bn
Bn
L2
L1
L3
O
Bn
N
O
N
O
O
O
O
O
N
N
N
N
N
N
Bn
Bn
Bn
Bn
18
L5
L4
L6
L518 also catalyzed the reaction to afford the product in 80% ee and
83% ee, respectively (entries 4 and 5, Table 2). However, ligands L2,
L3, and L6 were ineffective (entries 2, 3, and 6, Table 2). On the basis
of these results, we defined 1.0 equiv of 1b, 1.2 equiv of 2a,
0.45 equiv of Ag3PO4, 5 mol % of Pd(dba)2, and 10 mol % of (R,R)-Bn-
BOX(L1) in THF at 70 ꢀC as the standard reaction conditions.
With the optimized reaction conditions in hand, we studied the
scope of this catalytic stereoselective cyclization reaction with re-
spect to organic halides and allenylic hydrazines (Table 3). As
shown in Table 3, pyrazolidines were obtained in good yields with
good enantiopurity (>80%) in most cases. Not only aryl halides with
electron-donating and -withdrawing groups could be used in this
reaction (entries 2–9, Table 3), heteroaryl and 1-alkenyl iodides are
also suitable substrates (entries 10–13, Table 3). Moreover, (S,S)-
Bn-BOX can also catalyze the reaction to form the opposite enan-
tiomer in comparable yield and ee value (entry 14, Table 3).
Since all the pyrazolidines obtained above are viscous oils, we
tried to vary R1 and R2 groups on the substrate, intending to prepare
a solid product to elucidate the absolute configuration of the
products (entries 15 and 16, Table 3), but all efforts proved to be
fruitless. Thus, tentative assignment on the configuration in the
products was made based on the previous results in our group.16,17
By using (R,R)-Bn-BOX as the ligand, the reaction of (R), (S), or
racemic 2-(N,N-bis-(benzyloxycarbonyl)hydrazino)-2-(20,30-buta-
dienyl)-3-oxobutyric acid ethyl ester with phenyl iodide all affor-
ded the 5S-isomers as the major products. In consideration of the
similarity of these two systems, the absolute configuration of
Table 1
The effect of solvent and base on the Pd-catalyzed enantioselective coupling–
cyclization of 1a with PhIa
Ph
CO2Bn
5 mol% Palladium
HN
N
CO2Bn
10 mol% (R,R)-Bn-BOX
N
CO2Bn
+
PhI
N
n equiv Ag3PO4
solvent
CO2Bn
CO2Me
3aa
CO2Me
1a
MeO2C
MeO2C
Entry
Solvent
n equiv
Ag3PO4
Temperature
(ꢀC)
Yield of
eec (%)
3aab (%)
1
2
3
4
5
6
7
8e
DMF
0.4
0.4
0.4
0.4
0.4
0.45
0.5
80
80
80
80
80
80
80
70
72
69
68
57
54
67
61
75
63
71
62
77
81
82
82
84
1,4-Dioxane
Toluene
THF/DMFd
THF
THF
THF
THF
0.45
a
The reaction was carried out using 0.2 mmol of 1a, 0.24 mmol of PhI,
0.2ꢁn mmol of Ag3PO4, 5 mol % of Pd(OAc)2, and 10 mol % of (R,R)-Bn-BOX in 2 mL of
solvent in a Schlenk tube with a screw cap unless otherwise stated.
b
Isolated yields.
The ee values were determined by chiral HPLC analysis.
c
d
THF/DMF¼1:1.
e
Pd(dba)2 (5 mol %) and (R,R)-Bn-BOX (10 mol %) were used.

W. Shu et al. / Tetrahedron 64 (2008) 11159–11166
11161
Table 3
Br
Br
Pd-catalyzed enantioselective coupling–cyclization reaction of 1 with different
organic halidesa
CO2Et
R2
(1) 5 mol% Cu(OTf)2
5 mol% (S)-Ph-BOX
DCM, rt
CO2Bn
CO2Bn
CO2R1
CO2R1
CO2R1
+
5 mol% Pd(dba)2
HN
N
CO2R1
N
O
(1)
N
10 mol% (R,R)-Bn-BOX
N
+
N
N
R2I
CO2Bn
CO2Et
+
CO2Bn
CO2Et
(2) 5 mol% Pd(PPh3)4
2 equiv K2CO3
N
CO2R1
CO2R1
( )-3
0.45 equiv Ag3PO4
THF, 70 °C
O
O
BnO2C
R1O2C
R1O2C
N
N
1.2 equiv p-BrC6H4I
dioxane, 100 °C
(3 , 5 )-4dg
(3 , 5 )-4dg
Confirmed by X-ray16
1b-1c
2a-2n
CO2Bn
Confirmed by X-ray16
Entry
R1
R2I
Yield of 3b (%)
eec (%)
1
2
3
4
5
6
7
8
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Bn (1b)
Et (1c)
C6H5I (2a)
4-MeC6H4I (2b)
3-MeC6H4I (2c)
4-MeOC6H4I (2d)
4-MeO2CC6H4I (2e)
4-MeOCC6H4I (2f)
4-BrC6H4I (2g)
4-NCC6H4I (2h)
4-PhC6H4I (2i)
(E)-n-C4H9C2H2I (2j)
(E)-PhC2H2I (2k)
3-Oxocyclohexenyl iodide (2l)
2-Iodothiophene (2m)
4-BrC6H4I (2g)
4-(40-BrC6H4)C6H4I (2n)
4-BrC6H4I (2g)
74 (3ba)
72 (3bb)
68 (3bc)
77 (3bd)
71 (3be)
63 (3bf)
75 (3bg)
69 (3bh)
74 (3bi)
51 (3bj)
71 (3bk)
73 (3bl)
70 (3bm)
75 (R-3bg)
70 (3bn)
70 (3cg)
83
82
83
84
81
81
80
81
81
80
75
77
82
81
84
79
for the details of these data), we concluded that the absolute con-
figuration of the product 4dg prepared according to Scheme 2 is
(3S,5S). Based on this, the absolute configuration of the product 3dg
prepared with (R,R)-Bn-Box as the ligand has been confirmed to be S.
3. Conclusion
9
10
11
12
13
14d
15
16
We have demonstrated an enantioselective route to synthesize
optically active pyrazolidines from easily available 3,4-allenylic
hydrazines in the presence of organic halides. Further study in this
area is being pursued in our laboratory.
a
The reaction was carried out using 0.1–0.15 mmol of 1,1.2 equiv of R2I, 0.45 equiv
of Ag3PO4, 5 mol % of Pd(dba)2, and 10 mol % of (R,R)-Bn-BOX in 2 mL of THF in
a Schlenk tube with a screw cap.
4. Experimental section
4.1. General
b
Isolated yields.
The ee values were determined by chiral HPLC analysis.
Pd(dba)2 (5 mol %) and (S,S)-Bn-BOX (10 mol %) were used.
c
d
All reactions were carried out in a flame-dried Schlenk tube
with a screw cap under argon atmosphere unless otherwise stated.
THF and diethyl ether were dried over sodium wire with benzo-
phenone as the indicator and distilled freshly before use. DCM and
1,4-dioxane were dried over CaH2 and distilled freshly before use.
products 3 from reactions catalyzed by Pd(dba)2 and (R,R)-Bn-BOX
was tentatively assigned to be S.
In order to further confirm the absolute configuration of the
products, the tentatively assigned product (S)-3dg (81% ee), which
was prepared from the reaction of 1d and 4-bromophenyl iodide 2g
under the standard reaction conditions, was treated with MeMgBr
in Et2O, during which one of the ethoxycarbonyl group was reacted
with MeMgBr to form the acyl group to afford a new product 4dg.
Ascomparedwiththespectra, HPLCanalysis, andspecificrotation
measurement of the authentic sample (3R,5R)-4dg prepared from
our previous study (Eq. 1, see pages S81–S89 of Supplementary data
4.2. Preparation of starting materials
4.2.1. Synthesis of dimethyl 2-(10,20-bis(benzyloxycarbonyl)
hydrazinyl)-2-(200,300-butadienyl)malonate (1a)17
Under an argon atmosphere, Cu(OTf)2 (36 mg, 0.099 mmol),
(R,R)-Ph-BOX (47 mg, 0.14 mmol), and 5 mL of dichloromethane
were sequentially added into a flame-dried three-necked flask.
After stirring at rt for 1 h, dimethyl 2-(20,30-butadienyl)malonate
Br
5 mol% Pd(dba)2
10 mol% (R,R)-Bn-BOX
CO2Bn
HN
0.45 equiv Ag3PO4
CO2Bn
N
+
Br
I
CO2Bn
N
THF, 70 °C, 38 h
N
CO2Bn
CO2Et
( )-3dg
72% yield, 81% ee
EtO2C CO2Et
EtO2C
2g
1d
Br
1.1 equiv MeMgBr
-78 °C, Et2O, 3.5 h
CO2Bn
N
N
CO2Bn
CO2Et
O
(3 ,5 )-4dg
30% yield, 88% ee
Scheme 2. Synthesis of (3S,5S)-4dg.

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W. Shu et al. / Tetrahedron 64 (2008) 11159–11166
(184 mg, 1.00 mmol), dibenzyl azodicarboxylate (600 mg, 1.21 mmol),
and 5 mL of dichloromethane were added sequentially, and then
the resulting solution was stirred at rt. When the reaction was
finished as monitored by TLC, the solvent was removed under
vacuum, and the residue was purified by flash chromatography on
silica gel (eluent: petroleum ether/ethyl acetate¼30:1 to 10:1 to
5:1) to afford 1a (425 mg, 88%) as a viscous oil. 1H NMR (300 MHz,
Filtration and chromatography on silica gel (eluent: petroleum
ether/ethyl acetate¼10:1 to 5:1) afforded 81 mg of (S)-3ba (74%) as
a viscous oil; 83% ee (determined by HPLC analysis (Chiralcel AD,
20% i-PrOH in hexane, 0.7 mL/min, 214 nm), tR 52.4 (minor), 58.3
20
(major)); [
d
a
]
D
þ3.6 (c 1.35, EtOAc); 1H NMR (300 MHz, CDCl3):
7.38–7.18 (m, 21H), 7.18–7.07 (m, 4H), 5.66 (s, 1H), 5.53 (m, 1H),
5.23–4.86 (m, 9H), 3.11 (dd, J¼13.5, 8.7 Hz, 1H), 2.58 (dd, J¼13.5,
CDCl3):
d
7.38–7.23 (m, 10H), 6.88–6.63 (m, 1H), 5.27–5.04 (m, 5H),
2.7 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d
167.7, 166.0, 157.0, 153.3,
4.65–4.61 (m, 2H), 3.78–3.58 (m, 6H), 2.98–2.79 (m, 2H). It is very
difficult to purify this compound, thus, it was used in the enan-
tioselective cyclization directly without further characterization.
143.6, 138.4, 135.5, 135.3, 134.8, 134.4, 128.39, 128.38, 128.35, 128.2,
128.15, 128.11, 128.07, 127.9, 127.8, 127.6, 126.6, 113.7, 72.2, 68.4,
68.3, 68.2, 68.0, 61.2, 41.3; MS (ESI): m/z 749 (MþKþ), 733 (MþNaþ),
728 (MþNHþ4 ), 711 (Mþþ1); IR (neat): 1740, 1498, 1455, 1398, 1340,
1277, 1190, 1069; HRMS: calcd for C43H38N2O8 [MþNaþ]: 733.2520;
found: 733.2500.
4.2.2. Synthesis of dibenzyl 2-(10,20-bis(benzyloxycarbonyl)
hydrazinyl)-2-(200,300-butadienyl)malonate (1b)
The reaction of Cu(OTf)2 (90 mg, 0.25 mmol), (R,R)-Ph-BOX
(90 mg, 0.27 mmol), dibenzyl 2-(20,30-butadienyl)malonate (520 mg,
1.42 mmol), and dibenzyl azodicarboxylate (610 mg, 1.84 mmol) in
CH2Cl2 (20 mL) afforded 1b (693 mg, 77%) as a viscous oil. 1H NMR
4.3.2. 1,2-Bis(benzyloxycarbonyl)-3,3-bis(methoxycarbonyl)-5-
(10-phenylethenyl)pyrazolidine (S-3aa)
The reaction of 5 mol % Pd(OAc)2,10 mol % (R,R)-Bn-BOX, Ag3PO4
(34 mg, 0.081 mmol), 1a (97 mg, 0.20 mmol), and 2a (50 mg,
0.25 mmol) in THF (2 mL) afforded 60 mg of (S)-3aa (54%) as a vis-
cous oil; 81% ee (determined by HPLC analysis (Chiralcel OD, 25%
(300 MHz, CDCl3):
d 7.40–7.18 (m, 20H), 6.82–6.61 (m, 1H), 5.38–
4.97 (m, 9H), 4.58–4.46 (m, 2H), 3.15–2.90 (m, 2H); MS (ESI): m/z
657 (MþNaþ), 635 (Mþþ1); IR (neat): 3318, 1956, 1740, 1608, 1587,
1498, 1455, 1394, 1306; HRMS: calcd for C37H34N2O8 [MþNaþ]:
657.2207; found: 657.2205.
i-PrOH in hexane, 0.7 mL/min, 230 nm), tR 13.0 (minor), 16.3 (ma-
jor)); [
a]
þ12.0 (c 0.66, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.38–
20
D
7.27 (m, 15H), 5.64 (s, 1H), 5.49 (m, 1H), 5.31–5.10 (m, 5H), 3.59 (s,
4.2.3. Synthesis of diethyl 2-(10,20-bis(ethoxycarbonyl)hydrazinyl)-
2-(200,300-butadienyl)malonate (1c)
6H), 3.07 (dd, J¼13.8, 8.7 Hz, 1H), 2.56 (dd, J¼13.8, 3.3 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3):
d 168.5, 166.5, 157.0, 153.4, 144.2, 138.7,
The reaction of Cu(OTf)2 (40 mg, 0.11 mmol), (R,R)-Ph-BOX
(36 mg, 0.10 mmol), diethyl 2-(20,30-butadienyl)malonate (212 mg,
1.0 mmol), and diethyl azodicarboxylate (250 mg, 1.2 mmol) in
CH2Cl2 (10 mL) afforded 1c (328 mg, 85%) as a viscous oil. 1H NMR
135.5, 135.4, 128.5, 128.4, 128.1, 127.9, 127.7, 126.6, 113.5, 72.0, 68.5,
68.3, 61.4, 53.3, 53.1, 41.5; MS (MALDI): m/z 597 (MþKþ), 581
(MþNaþ); IR (neat): 1743, 1498, 1455, 1399, 1344, 1263, 1214, 1072;
HRMS: calcd for C31H30N2O8 [MþNaþ]: 581.1894; found: 581.1896.
(300 MHz, CDCl3):
d 6.52–6.26 (m, 1H), 5.37–5.26 (m, 1H), 4.68–
4.60 (m, 2H), 4.32–4.10 (m, 8H), 3.01–2.80 (m, 2H), 1.34–1.19 (m,
12H); MS (ESI): m/z 409 (MþNaþ), 387 (Mþþ1); IR (neat): 3313,
1957, 1740, 1468, 1445, 1375, 1304, 1228, 1096, 1068; HRMS: calcd
for C17H26N2O8 [MþNaþ]: 409.1581; found: 409.1599.
4.3.3. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-methyl
phenyl)ethenyl)pyrazolidine (S-3bb)
The reaction of Pd(dba)2 (4 mg, 0.0071 mmol), (R,R)-Bn-BOX
(5 mg, 0.014 mmol), Ag3PO4 (28 mg, 0.067 mmol), 1b (93 mg,
0.15 mmol), and 2b (41 mg, 0.19 mmol) in THF (2 mL) afforded
76 mg of (S)-3bb (72%) as a viscous oil; 83% ee (determined by HPLC
4.2.4. Synthesis of diethyl 2-(10,20-bis(benzyloxycarbonyl)
hydrazinyl)-2-(200,300-butadienyl)malonate (1d)
The reaction of Cu(OTf)2 (7 mg, 0.019 mmol), (R,R)-Ph-BOX
(7 mg, 0.021 mmol), diethyl 2-(20,30-butadienyl)malonate (44 mg,
0.21 mmol), and dibenzyl azodicarboxylate (79 mg, 0.24 mmol)
afforded 1d (57 mg, 54%) as a viscous oil. 1H NMR (300 MHz,
analysis (Chiralcel OD, 40% i-PrOH in hexane, 0.5 mL/min, 214 nm),
20
tR 8.2 (minor), 10.2 (major)); [
(300 MHz, CDCl3):
a]
þ9.6 (c 1.10, EtOAc); 1H NMR
D
d
7.39–7.19 (m, 18H), 7.16–7.02 (m, 6H), 5.64 (s,
1H), 5.54 (m, 1H), 5.26–4.88 (m, 9H), 3.12 (dd, J¼13.5, 8.7 Hz, 1H),
2.52 (dd, J¼13.5, 3.0 Hz, 1H), 2.35 (s, 3H); 13C NMR (75.4 MHz,
CDCl3):
d
7.39–7.22 (m, 10H), 6.78–6.49 (m, 1H), 5.38–5.10 (m, 5H),
CDCl3): d 167.7, 166.0, 157.0, 153.3, 143.3, 137.5, 135.5, 135.4, 135.3,
4.65–4.60 (m, 2H), 4.22–4.03 (m, 4H), 3.02–2.84 (m, 2H), 1.22–1.03
(m, 6H); MS (ESI): m/z 533 (MþNaþ), 511 (Mþþ1); IR (neat): 3308,
1957,1740,1499,1456,1392,1304,1218,1159,1069; HRMS: calcd for
C27H30N2O8 [MþNaþ]: 533.1894; found: 533.1911.
134.8, 134.4, 129.0, 128.4, 128.34, 128.30, 128.13, 128.10, 128.06,
128.0, 127.9, 127.6, 126.4, 112.9, 72.1, 68.4, 68.2, 68.1, 68.0, 61.2, 41.3,
21.0; MS (ESI): m/z 763 (MþKþ), 747 (MþNaþ); IR (neat): 1739,
1498, 1455, 1398, 1339, 1276, 1191, 1069; HRMS: calcd for
C44H40N2O8 [MþNaþ]: 747.2677; found: 747.2655.
Due to the presence of four different conformations and severe
rotameric broadening of many of signals, the NMR spectra for these
compounds are in general complicated.19 13C NMR spectra are just
attached in Supplementary data.
4.3.4. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(300-methyl
phenyl)ethenyl)pyrazolidine (S-3bc)
The reaction of Pd(dba)2 (4 mg, 0.0071 mmol), (R,R)-Bn-BOX
(6 mg, 0.016 mmol), Ag3PO4 (28 mg, 0.067 mmol), 1b (96 mg,
0.15 mmol), and 2c (39 mg, 0.18 mmol) in THF (2 mL) afforded
74 mg of (S)-3bc (68%) as a viscous oil; 83% ee (determined by HPLC
4.3. Palladium-catalyzed enantioselective cyclization of 3,4-
allenylic hydrazines with organic halides
4.3.1. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-phenylethenyl)-
pyrazolidine (S-3ba)
analysis (Chiralcel OD, 40% i-PrOH in hexane, 0.5 mL/min, 214 nm),
20
tR 8.0 (minor), 9.7 (major)); [
a
]
þ3.3 (c 0.85, EtOAc); 1H NMR
D
Typical procedure. To a Schlenk tube with a screw cap were
added Pd(dba)2 (4 mg, 0.0071 mmol), Ag3PO4 (27 mg, 0.064 mmol),
(R,R)-Bn-BOX (6 mg, 0.016 mmol), and 1 mL of THF. The resulting
mixture was stirred for 1 h at rt, which was followed by sequential
introduction of 1b (97 mg, 0.15 mmol), 1 mL of THF, and phenyl
iodide 2a (37 mg, 0.18 mmol) at rt. The resulting solution was
stirred at 70 ꢀC. When the reaction was completed as monitored by
TLC, the mixture was extracted by ether, and the organic layer was
washed by water and brine, then dried over sodium sulfate.
(300 MHz, CDCl3): d 7.39–7.05 (m, 22H), 6.99–6.90 (m, 2H), 5.64 (s,
1H), 5.52 (m, 1H), 5.24–4.84 (m, 9H), 3.11 (dd, J¼13.2, 8.4 Hz, 1H),
2.59 (dd, J¼13.2, 2.4 Hz, 1H), 2.30 (s, 3H); 13C NMR (75.4 MHz,
CDCl3):
d 167.8, 166.0, 157.0, 153.3, 143.7, 138.4, 138.0, 135.6, 135.4,
134.9, 134.4, 128.6, 128.42, 128.38, 128.35, 128.3, 128.2, 128.15,
128.12, 128.07, 128.0, 127.6, 127.2, 123.6, 113.4, 72.2, 68.4, 68.3, 68.2,
68.0, 61.3, 41.4, 21.4; MS (ESI): m/z 763 (MþKþ), 747 (MþNaþ); IR
(neat): 1738, 1498, 1455, 1397, 1339, 1276, 1188, 1069; HRMS: calcd
for C44H40N2O8 [MþNaþ]: 747.2677; found: 747.2653.

W. Shu et al. / Tetrahedron 64 (2008) 11159–11166
11163
4.3.5. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-methoxyl
phenyl)ethenyl)pyrazolidine (S-3bd)
J¼13.5, 9.0 Hz, 1H), 2.52 (dd, J¼13.5, 2.1 Hz, 1H); 13C NMR
(75.4 MHz, CDCl3):
d 167.7, 165.9, 157.0, 153.2, 142.7, 137.4, 135.5,
The reaction of Pd(dba)2 (4 mg, 0.0071 mmol), (R,R)-Bn-BOX
(6 mg, 0.016 mmol), Ag3PO4 (28 mg, 0.067 mmol), 1b (99 mg,
0.16 mmol), and 2d (42 mg, 0.18 mmol) in THF (2 mL) afforded
89 mg of (S)-3bd (77%) as a viscous oil; 84% ee (determined by HPLC
135.3, 134.8, 134.4, 131.5, 128.5, 128.44, 128.41, 128.23, 128.22, 128.1,
128.0, 127.7, 121.8, 114.5, 72.2, 68.6, 68.3, 68.2, 68.1, 61.1, 41.2;
MS (ESI): m/z 829 (M(81Br)þKþ), 827 (M(79Br)þKþ), 813
(M(81Br)þNaþ), 811 (M(79Br)þNaþ); IR (neat): 1736, 1587, 1498,
1490, 1455, 1394, 1341, 1274, 1190, 1071; HRMS: calcd for
C43H37N2O8Br [M(79Br)þNaþ]: 811.1626; found: 811.1611.
analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.5 mL/min, 230 nm),
20
tR 31.6 (minor), 38.3 (major)); [
(300 MHz, CDCl3):
a]
þ12.0 (c 0.95, EtOAc); 1H NMR
D
d
7.38–7.18 (m, 18H), 7.13–7.01 (m, 4H), 6.79 (d,
J¼8.4 Hz, 2H), 5.58 (s, 1H), 5.48 (m, 1H), 5.24–4.85 (m, 9H), 3.79 (s,
4.3.9. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-
cyanophenyl)ethenyl)pyrazolidine (S-3bh)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(4 mg, 0.011 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1b (63 mg,
0.099 mmol), and 2h (30 mg, 0.13 mmol) in THF (2 mL) afforded
50 mg of (S)-3bh (68%) as a viscous oil; 81% ee (determined by
3H), 3.10 (dd, J¼13.5, 9.0 Hz, 1H), 2.60 (dd, J¼13.5, 2.4 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3):
d
167.8, 166.0, 159.2, 157.0, 153.3, 142.9,
135.6, 135.4, 134.9, 134.4, 130.8, 128.43, 128.39, 128.36, 128.17,
128.12, 128.08, 128.0, 127.7, 127.6, 113.7, 112.3, 72.2, 68.4, 68.3, 68.2,
68.0, 61.3, 55.2, 41.3; MS (ESI): m/z 764 (MþNaþ), 758 (MþNH4þ),
741 (Mþþ1); IR (neat): 1739, 1608, 1513, 1455, 1398, 1339, 1271,
1249, 1188, 1069; HRMS: calcd for C44H40N2O9 [MþNaþ]: 763.2626;
found: 763.2608.
HPLC analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min,
20
214 nm), tR 20.6 (minor), 36.7 (major)); [
a
]
þ8.9 (c 0.95, EtOAc);
D
1H NMR (300 MHz, CDCl3):
d
7.47 (d, J¼8.7 Hz, 2H), 7.39–7.17 (m,
18H), 7.16–7.04 (m, 4H), 5.72 (s, 1H), 5.45 (m, 1H), 5.23–4.83 (m,
4.3.6. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-methoxyl
carbonylphenyl)ethenyl)pyrazolidine (S-3be)
9H), 3.11 (dd, J¼13.5, 8.7 Hz, 1H), 2.47 (dd, J¼13.5, 2.7 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3):
d 167.5, 165.9, 156.9, 153.2, 143.1, 142.7,
The reaction of Pd(dba)2 (4 mg, 0.0071 mmol), (R,R)-Bn-BOX
(6 mg, 0.016 mmol), Ag3PO4 (28 mg, 0.067 mmol), 1b (93 mg,
0.15 mmol), and 2e (49 mg, 0.19 mmol) in THF (2 mL) afforded
80 mg of (S)-3be (71%) as a viscous oil; 81% ee (determined by HPLC
135.3, 135.2, 134.7, 134.3, 132.1, 128.6, 128.4, 128.3, 128.24, 128.20,
128.0, 127.7, 127.3, 118.5, 116.7, 111.3, 72.1, 68.6, 68.4, 68.3, 68.1,
60.9, 41.1; MS (ESI): m/z 774 (MþKþ), 758 (MþNaþ); IR (neat):
2227, 1736, 1606, 1587, 1498, 1455, 1400, 1341, 1277, 1191, 1069;
HRMS: calcd for C44H37N3O8 [MþNaþ]: 758.2473; found:
758.2481.
analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.5 mL/min, 214 nm),
20
tR 48.9 (minor), 65.8 (major)); [
(300 MHz, CDCl3):
a
]
D
þ12.5 (c 1.05, EtOAc); 1H NMR
d
7.91 (d, J¼8.1 Hz, 2H), 7.35–7.05 (m, 22H), 5.73
(s, 1H), 5.52 (m, 1H), 5.26 (s, 1H), 5.22–4.84 (m, 8H), 3.92 (s, 3H),
4.3.10. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-
phenylphenyl)ethenyl)pyrazolidine (S-3bi)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(4 mg, 0.011 mmol), Ag3PO4 (20 mg, 0.048 mmol), 1b (63 mg,
0.099 mmol), and 2i (35 mg, 0.12 mmol) in THF (2 mL) afforded
58 mg of (S)-3bi (74%) as a viscous oil; 81% ee (determined by HPLC
3.13 (dd, J¼13.8, 8.7 Hz, 1H), 2.51 (dd, J¼13.8, 2.7 Hz, 1H); 13C NMR
(75.4 MHz, CDCl3):
d
167.6, 166.6, 165.9, 156.9, 153.2, 143.0, 142.9,
135.4, 135.2, 134.8, 134.3, 129.6, 129.3, 128.5, 128.40, 128.36, 128.2,
128.1, 127.9, 127.6, 126.5, 115.5, 72.1, 68.5, 68.3, 68.2, 68.0, 61.0, 52.1,
41.2; MS (ESI): m/z 807 (MþKþ), 791 (MþNaþ), 769 (Mþþ1); IR
(neat): 1720, 1608, 1498, 1455, 1402, 1279, 1189, 1069; HRMS: calcd
for C45H40N2O10 [MþNaþ]: 791.2575; found: 791.2561.
analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min, 230 nm),
20
tR 13.7 (minor), 22.4 (major)); [
a
]
þ14.7 (c 1.10, EtOAc); 1H NMR
D
(300 MHz, CDCl3):
d
7.60–7.56 (m, 2H), 7.53–7.42 (m, 4H), 7.40–7.17
4.3.7. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-acetyl
phenyl)ethenyl)pyrazolidine (S-3bf)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(4 mg, 0.011 mmol), Ag3PO4 (20 mg, 0.048 mmol), 1b (69 mg,
0.11 mmol), and 2f (37 mg, 0.15 mmol) in THF (2 mL) afforded
51 mg of (S)-3bf (63%) as a viscous oil; 81% ee (determined by
(m, 21H), 7.11–7.06 (m, 2H), 5.69 (s, 1H), 5.57 (m, 1H), 5.29–4.85 (m,
9H), 3.15 (dd, J¼13.5, 9.0 Hz, 1H), 2.64 (dd, J¼13.5, 2.4 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3): d 167.8, 166.0, 157.0, 153.3, 143.1, 140.6,
140.4, 137.3, 135.6, 135.4, 134.9, 134.4, 128.8, 128.44, 128.43, 128.40,
128.38, 128.2, 128.15, 128.11, 128.0, 127.7, 127.4, 127.1, 126.9, 72.2,
68.5, 68.3, 68.2, 68.0, 61.2, 41.4; MS (ESI): m/z 825 (MþKþ), 809
(MþNaþ); IR (neat): 1738, 1498, 1488, 1455, 1399, 1340, 1274, 1189,
1069; HRMS: calcd for C49H42N2O8 [MþNaþ]: 809.2833; found:
809.2801.
HPLC analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min,
20
214 nm), tR 19.5 (minor), 31.6 (major)); [
a]
þ15.3 (c 1.35, EtOAc);
D
1H NMR (300 MHz, CDCl3):
d
7.81 (d, J¼8.7 Hz, 2H), 7.38–7.14 (m,
20H), 7.10–7.05 (m, 2H), 5.72 (s, 1H), 5.52 (m, 1H), 5.26 (s, 1H),
5.21–4.82 (m, 8H), 3.11 (dd, J¼13.2, 8.4 Hz, 1H), 2.57 (s, 3H), 2.54
4.3.11. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-methylene-20(E)-
heptenyl)pyrazolidine (S-3bj)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(4 mg, 0.011 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1b (63 mg,
0.099 mmol), and 2j (29 mg, 0.14 mmol) in THF (2 mL) afforded
37 mg of (S)-3bj (51%) as a viscous oil; 78% ee (determined by
(dd, J¼13.2, 2.1 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d 197.4, 167.6,
165.9, 157.0, 153.2, 143.1, 142.9, 136.2, 135.4, 135.2, 134.8, 134.3,
128.44, 128.38, 128.22, 128.18, 128.1, 128.0, 127.6, 126.7, 115.7, 72.1,
68.6, 68.3, 68.2, 68.1, 61.0, 41.2, 26.5; MS (ESI): m/z 791 (MþKþ),
775 (MþNaþ); IR (neat): 1736, 1683, 1604, 1498, 1455, 1401, 1341,
1267, 1189, 1068; HRMS: calcd for C45H40N2O9 [MþNaþ]:
775.2626; found: 775.2597.
HPLC analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min,
20
230 nm), tR 8.5 (minor), 10.0 (major)); [
a
]
ꢂ11.1 (c 1.15, EtOAc);
D
1H NMR (300 MHz, CDCl3):
d
7.36–7.13 (m, 20H), 5.92 (d,
4.3.8. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-bromo
phenyl)ethenyl)pyrazolidine (S-3bg)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(4 mg, 0.011 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1b (64 mg,
0.10 mmol), and 2g (37 mg, 0.15 mmol) in THF (2 mL) afforded
60 mg of (S)-3bg (75%) as a viscous oil; 80% ee (determined by HPLC
J¼16.8 Hz, 1H), 5.44 (dt, J¼16.8, 6.9 Hz, 1H), 5.38 (s, 1H), 5.20–4.83
(m, 10H), 3.20 (dd, J¼13.2, 8.7 Hz, 1H), 2.73 (dd, J¼13.2, 3.3 Hz, 1H),
2.07–2.00 (m, 2H), 1.38–1.22 (m, 4H), 0.89 (t, J¼7.2 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3):
d 167.9, 165.9, 156.8, 153.2, 141.5, 135.6,
135.3, 134.9, 134.5, 131.3, 129.1, 128.4, 128.3, 128.2, 128.10, 128.06,
127.99, 127.96, 127.6, 113.7, 72.2, 68.3, 68.2, 68.0, 59.6, 42.0, 32.7,
31.2, 22.2, 13.9; MS (ESI): m/z 755 (MþKþ), 739 (MþNaþ), 717
(Mþþ1); IR (neat): 1736, 1498, 1456, 1398, 1341, 1270, 1190, 1071;
HRMS: calcd for C43H44N2O8 [MþNaþ]: 739.2990; found:
739.3000.
analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min, 230 nm),
20
tR 11.7 (minor), 18.4 (major)); [
(300 MHz, CDCl3):
a]
þ7.8 (c 0.95, EtOAc); 1H NMR
D
d
7.38–7.18 (m, 20H), 7.12–7.06 (m, 2H), 6.94 (d,
J¼8.4 Hz, 2H), 5.65 (s, 1H), 5.44 (m, 1H), 5.21–4.83 (m, 9H), 3.09 (dd,

11164
W. Shu et al. / Tetrahedron 64 (2008) 11159–11166
4.3.12. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-methylene-30-
phenyl-20(E)-propenyl)pyrazolidine (S-3bk)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX (4 mg,
0.011 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1b (63 mg, 0.099 mmol),
and 2k (29 mg, 0.13 mmol) in THF (2 mL) afforded 52 mg of (S)-3bk
(71%)as aviscousoil;75%ee (determinedbyHPLCanalysis(ChiralcelOD,
40% i-PrOH in hexane, 0.5 mL/min, 214 nm), tR 12.4 (minor), 15.3 (ma-
(75.4 MHz, CDCl3): d 167.6, 165.9, 157.0, 153.2, 142.7, 137.4, 135.4,
135.3, 134.8, 134.3, 131.5, 128.5, 128.42, 128.40, 128.2, 128.1, 128.0,
127.7, 121.8, 114.5, 72.1, 68.5, 68.3, 68.2, 68.1, 61.1, 41.2; MS (MALDI):
m/z 829 (M(81Br)þKþ), 827 (M(79Br)þKþ), 813 (M(81Br)þNaþ), 811
(M(79Br)þNaþ); IR (neat): 1738, 1587, 1498, 1455, 1394, 1345, 1273,
1189, 1071; HRMS: calcd for C43H37N2O8Br [M(79Br)þNaþ]:
811.1626; found: 811.1617.
jor)); [a 2D0
]
þ3.0 (c 1.05, EtOAc); 1H NMR (300 MHz, CDCl3):
d 7.38–7.18
(m, 23H), 7.17–7.10 (m, 2H), 6.66 (d, J¼16.8 Hz, 1H), 6.34 (d, J¼16.8 Hz,
4.3.16. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-(4%-bromo
phenyl)phenyl)ethnyl)pyrazolidine (S-3bn)
The reaction of Pd(dba)2 (4 mg, 0.0071 mmol), (R,R)-Bn-BOX
(5 mg, 0.014 mmol), Ag3PO4 (20 mg, 0.048 mmol), 1b (65 mg,
0.10 mmol), and 2n (46 mg, 0.13 mmol) in THF (2 mL) afforded
62 mg of (S)-3bn (70%) as a viscous oil; 84% ee (determined by HPLC
1H), 5.59 (s,1H), 5.29 (m,1H), 5.21–4.90 (m, 9H), 3.33 (dd, J¼13.5, 9.0 Hz,
1H), 2.83 (dd, J¼13.5, 3.3 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d
167.8,
165.9, 156.8, 153.2, 141.5, 136.6, 135.5, 135.3, 134.9, 134.4, 128.9, 128.6,
128.4,128.3,128.23,128.17,128.13,128.08,128.0,127.8,127.6,126.4,116.7,
72.2, 68.5, 68.3, 68.14, 68.10, 59.6, 42.1; MS (ESI): m/z 775 (MþKþ), 759
(MþNaþ); IR (neat): 1736, 1607, 1497, 1455, 1398, 1341, 1271, 1190, 1070;
HRMS: calcd for C45H40N2O8 [MþNaþ]: 759.2677; found: 759.2665.
analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min, 230 nm),
20
tR 20.8 (minor), 33.0 (major)); [
a
]
þ13.7 (c 1.05, EtOAc); 1H NMR
D
(300 MHz, CDCl3):
d
7.56 (d, J¼8.4 Hz, 2H), 7.45–7.41 (m, 4H), 7.37–
4.3.13. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(300-
7.17 (m, 20H), 7.10–7.07 (m, 2H), 5.69 (s, 1H), 5.55 (m, 1H), 5.27 (s,
oxocyclohexenyl)ethenylpyrazolidine (S-3bl)
1H), 5.23–4.87 (m, 8H), 3.13 (dd, J¼13.5, 8.7 Hz, 1H), 2.62 (dd,
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(5 mg, 0.014 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1b (68 mg,
0.11 mmol), and 2l (35 mg, 0.16 mmol) in THF (2 mL) afforded
57 mg of (S)-3bl (73%) as a viscous oil; 77% ee (determined by HPLC
J¼13.5, 3.0 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d 167.7, 166.0,
153.3, 143.0, 139.26, 139.21, 137.7, 135.5, 135.3, 134.8, 134.4, 131.8,
128.44, 128.41, 128.36, 128.3, 128.2, 128.1, 127.9, 127.6, 127.0, 126.8,
121.6, 72.2, 68.5, 68.3, 68.2, 68.0, 61.1, 41.3; MS (ESI): m/z 889
(M(81Br)þNaþ), 887 (M(79Br)þNaþ), 867 (Mþ(81Br)þ1), 865
(Mþ(79Br)þ1); IR (neat): 1740, 1587, 1498, 1483, 1455, 1391, 1340,
1275, 1189, 1070; HRMS: calcd for C49H41N2O8Br [M(79Br)þNaþ]:
887.1938; found: 887.1924.
analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min, 214 nm),
20
tR 21.5 (minor), 24.6 (major)); [
(300 MHz, CDCl3):
a
]
D
þ1.4 (c 1.15, EtOAc); 1H NMR
d
7.38–7.17 (m, 18H), 7.12–7.08 (m, 2H), 5.86 (s,
1H), 5.79 (s, 1H), 5.39 (s, 1H), 5.24–4.85 (m, 9H), 3.25 (dd, J¼13.5,
8.7 Hz,1H), 2.60 (dd, J¼13.5, 2.7 Hz,1H), 2.47–2.31 (m, 3H), 2.09 (dt,
J¼18.0, 5.4 Hz, 1H), 2.01–1.80 (m, 2H); 13C NMR (75.4 MHz, CDCl3):
4.3.17. 1,2,3,3-Tetrakis(ethoxycarbonyl)-5-(10-(400-bromo
phenyl)ethenyl)pyrazolidine (S-3cg)
d
199.6, 167.4, 166.0, 156.6, 155.8, 153.0, 142.7, 135.3, 135.1, 134.7,
134.3, 128.5, 128.43, 128.38, 128.34, 128.30, 128.24, 128.17, 128.1,
127.7, 125.1, 118.6, 72.1, 68.6, 68.4, 68.23, 68.20, 59.5, 42.4, 37.2, 26.6,
22.2; MS (ESI): m/z 767 (MþKþ), 751 (MþNaþ), 729 (Mþþ1); IR
(neat): 1736, 1668, 1585, 1498, 1455, 1399, 1328, 1276, 1191, 1069;
HRMS: calcd for C43H40N2O9 [MþNaþ]: 751.2626; found: 751.2622.
The reaction of Pd(dba)2 (4 mg, 0.0071 mmol), (R,R)-Bn-BOX
(5 mg, 0.014 mmol), Ag3PO4 (26 mg, 0.062 mmol), 1c (54 mg,
0.14 mmol), and 2g (48 mg, 0.17 mmol) in THF (2 mL) afforded
53 mg of (S)-3cg (70%) as a viscous oil; 79% ee (determined by HPLC
analysis (Chiralcel AD, 40% i-PrOH in hexane, 0.7 mL/min, 230 nm),
20
tR 4.5 (minor), 5.2 (major)); [
(300 MHz, CDCl3):
a
]
þ20.7 (c 1.05, EtOAc); 1H NMR
D
4.3.14. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(200-thienyl)
ethenyl)pyrazolidine (S-3bm)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(5 mg, 0.014 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1b (49 mg,
0.077 mmol), and 2m (25 mg, 0.12 mmol) in THF (2 mL) afforded
39 mg of (S)-3bm (70%) as a viscous oil; 82% ee (determined by
d
7.45 (d, J¼8.1 Hz, 2H), 7.21 (d, J¼8.1 Hz, 2H),
5.67 (s, 1H), 5.39–5.33 (m, 2H), 4.3–4.10 (m, 8H), 3.02 (dd, J¼13.8,
9.0 Hz, 1H), 2.49 (dd, J¼13.8, 3.3 Hz, 1H), 1.32–1.23 (m, 9H), 1.19 (t,
J¼7.2 Hz, 3H); 13C NMR (75.4 MHz, CDCl3):
d 168.0, 166.1, 157.1,
153.5, 143.5, 137.7, 131.6, 128.3, 121.9, 114.1, 72.1, 63.1, 62.6, 62.5,
60.9, 41.4, 14.4, 13.9,13.7; MS (ESI): m/z 597 (M(81Br)þMeOHþNaþ),
HPLC analysis (Chiralcel OD, 40% i-PrOH in hexane, 0.5 mL/min,
595
(M(79Br)þMeOHþNaþ),
565
(M(81Br)þNaþ),
563
20
214 nm), tR 10.5 (minor),15.0 (major)); [
NMR (300 MHz, CDCl3):
a
]
D
þ3.0 (c 1.05, EtOAc); 1H
(M(79Br)þNaþ), 543 (Mþ(81Br)þ1), 541 (Mþ(79Br)þ1); IR (neat):
1747, 1488, 1466, 1404, 1377, 1336, 1303, 1276, 1196, 1073; HRMS:
calcd for C23H29N2O8Br [M(79Br)þNaþ]: 563.1000; found: 563.0996.
d
7.36–7.18 (m,19H), 7.11–7.05 (m, 2H), 6.94
(dd, J¼4.8, 3.6 Hz, 1H), 6.82 (d, J¼3.6 Hz, 1H), 5.55 (s, 1H), 5.38 (m,
1H), 5.33 (s, 1H), 5.20–4.84 (m, 8H), 3.25 (dd, J¼13.5, 9.3 Hz, 1H),
2.78 (dd, J¼13.5, 3.0 Hz, 1H); 13C NMR (75.4 MHz, CDCl3):
d
167.7,
4.3.18. 1,2-Bis(benzyloxycarbonyl)-3,3-bis(ethoxycarbonyl)-5-(10-
(400-bromophenyl)ethenyl)pyrazolidine (S-3dg)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (R,R)-Bn-BOX
(4 mg, 0.011 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1d (51 mg,
0.10 mmol), and 2g (34 mg, 0.12 mmol) in THF (2 mL) afforded
48 mg of (S)-3dg (72%) as a viscous oil; 81% ee (determined by HPLC
165.9, 156.8, 153.2, 141.6, 137.4, 135.5, 135.2, 134.8, 134.4, 128.42,
128.40, 128.35, 128.3, 128.2, 128.14, 128.09, 128.0, 127.6, 127.3, 124.6,
123.7, 112.4, 72.3, 68.5, 68.3, 68.2, 68.1, 61.0, 42.0; MS (ESI): m/z 755
(MþKþ), 739 (MþNaþ); IR (neat): 1736, 1498, 1455, 1398, 1342,
1276, 1190, 1070; HRMS: calcd for C41H36N2O8S [MþNaþ]:
739.2085; found: 739.2078.
analysis (Chiralcel OD, 15% i-PrOH in hexane, 0.7 mL/min, 230 nm),
20
tR 7.5 (minor), 12.2 (major)); [
(300 MHz, CDCl3):
a]
þ10.8 (c 1.25, EtOAc); 1H NMR
D
4.3.15. 1,2,3,3-Tetrakis(benzyloxycarbonyl)-5-(10-(400-bromo
phenyl)ethenyl)pyrazolidine (R-3bg)
The reaction of Pd(dba)2 (3 mg, 0.0053 mmol), (S,S)-Bn-BOX
(5 mg, 0.014 mmol), Ag3PO4 (19 mg, 0.045 mmol), 1b (60 mg,
0.094 mmol), and 2g (37 mg, 0.15 mmol) in THF (2 mL) afforded
56 mg of (R)-3bg (75%) as a viscous oil; 82% ee (determined by HPLC
d
7.43 (d, J¼8.4 Hz, 2H), 7.38–7.24 (m, 10H), 7.19
(d, J¼8.4 Hz, 2H), 5.67 (s, 1H),5.42 (m, 1H), 5.31 (s, 1H), 5.26 (d,
J¼12.3 Hz, 1H), 5.20 (s, 2H), 5.07 (d, J¼12.3 Hz, 1H), 4.20–3.97 (m,
4H), 3.07 (dd, J¼13.5, 9.0 Hz, 1H), 2.53 (dd, J¼13.5, 3.3 Hz, 1H), 1.11
(t, J¼7.2 Hz, 6H); 13C NMR (75.4 MHz, CDCl3):
d 167.9, 166.1, 156.9,
153.3, 143.2, 137.6, 135.5, 135.4, 131.6, 128.44, 128.35, 128.30, 128.2,
128.1, 127.6, 121.9, 114.4, 72.2, 68.6, 68.3, 62.5, 61.1, 41.3, 13.7, 13.6;
MS (ESI): m/z 689 (M(81Br)þNaþ), 687 (M(79Br)þNaþ), 666
(Mþ(81Br)þ1), 664 (Mþ(79Br)þ1); IR (neat): 1736, 1587, 1489, 1455,
1393, 1341, 1278, 1198, 1072; HRMS: calcd for C33H33N2O8Br
[M(79Br)þNaþ]: 687.1313; found: 687.1296.
analysis (Chiralcel AD, 25% i-PrOH in hexane, 0.7 mL/min, 230 nm),
20
tR 17.3 (major), 29.4 (minor)); [
(300 MHz, CDCl3):
a]
ꢂ6.8 (c 1.05, EtOAc); 1H NMR
D
d
7.38–7.08 (m, 20H), 7.10–7.07 (m, 2H), 6.94 (d,
J¼8.4 Hz, 2H), 5.65 (s,1H), 5.44 (m, 1H), 5.22–4.85 (m, 9H), 3.09 (dd,
J¼13.8, 9.0 Hz, 1H), 2.52 (dd, J¼13.8, 2.7 Hz, 1H); 13C NMR

W. Shu et al. / Tetrahedron 64 (2008) 11159–11166
11165
4.4. Determination of the absolute configurations of the
Supplementary data
products 3
1H/13C NMR spectra of all new compounds. This material is
available free of charge via the Internet. Supplementary data as-
sociated with this article can be found in the online version, at
doi:10.1016/j.tet.2008.09.049.
4.4.1. Synthesis of 1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-3-
acetyl-5-(10-(400-bromophenyl)ethenyl)pyrazolidine (4dg) ((3R,5R)-
4dg and (3R,5S)-4dg) from the reaction of ethyl 2-(20,30-
butadienyl)-3-oxobutyrate with dibenzyl azodicarboxylate16
A solution of Cu(OTf)2 (4 mg, 0.011 mmol) and (S,S)-Ph-BOX
(4 mg, 0.012 mmol) in 2 mL of CH2Cl2 was stirred at rt for 1 h. Then,
ethyl 2-(20,30-butadienyl)-3-oxobutyrate (18 mg, 0.099 mmol) and
dibenzyl azodicarboxylate (36 mg, 0.11 mmol) were added to the
solution at 0 ꢀC. The mixture was stirred at this temperature for 3 h
as monitored by TLC. Then, potassium carbonate (28 mg,
0.20 mmol), Pd(PPh3)4 (6 mg, 0.0050 mmol), p-bromoiodobenzene
(34 mg, 0.12 mmol), and 1,4-dioxane (2 mL) were sequentially
added into this mixture. The resulting mixture was heated at 100 ꢀC
for 4 h as monitored by TLC. After evaporation, the residue was
purified by flash chromatography on silica gel (eluent: petroleum
ether/ethyl acetate¼5:1) to afford 19 mg (29%) of (3R,5R)-4dg and
38 mg (60%) (3R,5S)-4dg.
References and notes
1. (a) Khau, V. V.; Martinelli, M. J. Tetrahedron Lett. 1996, 37, 4323–4326; (b)
Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G. Tetrahedron 1997, 53,
12789–12854; (c) Kim, H. O.; Lum, C.; Lee, M. S. Tetrahedron Lett. 1997, 38, 4935–
4938; (d) Kutterer, K. M. K.; Davis, J. M.; Singh, G.; Yang, Y.; Hu, W.; Severin, A.;
Rasmussen, B. A.; Krishnamurthy, G.; Faillic, A.; Katzc, A. H. Bioorg. Med. Chem.
Lett. 2005, 15, 2527–2531; (e) Ahn, J. H.; Kim, J. A.; Kim, H. M.; Kwon, H. M.;
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Cheon, H. G. Bioorg. Med. Chem. Lett. 2005, 15, 1337–1340; (f) Cheon, H. G.; Kim,
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2. For some reviews, see: (a) Huisgen, R.; Grashey, R.; Sauer, J. In The Chemistry of
Alkenes: Cycloaddition Reactions of Alkenes; Patai, S., Ed.; Interscience: New
York, NY, 1964; pp 739–953; (b) Huisgen, R. In 1,3-Dipolar Cycloaddition
Chemistry: 1,3-Dipolar Cycloaddition-Introduction, Survey, Mechanism; Padwa, A.,
Ed.; Wiley-Interscience: New York, NY, 1984; Vol. 1, pp 1–176; (c) Huisgen, R. In
Advance in Cycloaddition: Steric Course and Mechanism of 1,3-Dipolar Cycload-
dition; Curran, D. P., Ed.; JAI: Greenwich, CT, 1988; Vol. 1, pp 1–31; (d)
Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.; Kobayashi, J. J. Am. Chem.
Soc. 2002, 124, 13678–13679; (e) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am.
Chem. Soc. 1997, 119, 8379–8380; (f) Gallos, J. K.; Koumbis, A. E.; Apostolakis, N.
E. J. Chem. Soc., Perkin Trans. 1 1997, 2457–2459.
Compound (3R,5R)-4dg: >99% ee (determined by HPLC analysis
(Chiralcel OD, 2% i-PrOH in hexane, 0.7 mL/min, 230 nm), tR 21.2
20
20
(major), 23.7 (minor)); [
a
]
þ44.1 (c 0.50, EtOAc); [
a
]
þ45.3 (c
D
D
0.45, CHCl3) (lit.16 þ45.4); 1H NMR (CDCl3, 300 MHz):
d 7.41 (d,
J¼8.4 Hz, 2H), 7.40–7.19 (m, 10H), 7.17 (d, J¼8.4 Hz, 2H), 5.63 (s, 1H),
5.35 (m, 1H), 5.31–5.05 (m, 5H), 4.13–3.95 (m, 2H), 3.25 (dd, J¼13.5,
9.3 Hz, 1H), 2.34 (s, 3H), 2.21 (dd, J¼13.5, 3.0 Hz, 1H), 1.10 (t,
J¼7.5 Hz, 3H).
3. (a) Kobayashi, S.; Hirabayashi, R.; Shimizu, H.; Ishitani, H.; Yamashita, Y. Tet-
rahedron Lett. 2003, 44, 3351–3354; (b) Ja¨ger, V.; Bierer, L.; Dong, H. Q.; Palmer,
A. M.; Shaw, D.; Frey, W. J. Heterocycl. Chem. 2000, 37, 455–465.
4. Ellis, J. M.; King, S. B. Tetrahedron Lett. 2002, 43, 5833–5835.
5. Bonner, W. A. In Topics in Stereochemistry; Eliel, E., Wilen, S. H., Eds.; John Wiley
and Sons: New York, NY, 1988; Vol. 18, pp 1–96.
Compound (3R,5S)-4dg: 97% ee (determined by HPLC analysis
(Chiralcel OD, 15% i-PrOH in hexane, 0.7 mL/min, 230 nm), tR 9.2
20
20
D
6. For recent reports on synthesis of optically active pyrazolidines, see: (a) Guerra,
F. M.; Mish, M. R.; Carreira, E. M. Org. Lett. 2000, 2, 4265–4267; (b) Whitlock, G.
A.; Carreira, E. M. Helv. Chim. Acta 2000, 83, 2007–2022; (c) Barluenga, J.;
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Zlicar, M.; Svete, J. J. Heterocycl. Chem. 1998, 35, 1187–1204; (e) Rutjes, F. P. J. T.;
Teerhuis, N. M.; Hiemstra, H.; Speckhamp, W. N. Tetrahedron 1993, 49, 8605–
8628; (f) Chauveau, A.; Martens, T.; Bonin, M.; Micouin, L.; Husson, H. P. Syn-
thesis 2002, 1885–1890; (g) Yamashito, Y.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 11279–11282.
7. For recent reviews on transition metal-catalyzed reactions for synthesis of
heterocyclic compounds, see: (a) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev.
2004, 104, 2285–2310; (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127–2198; (c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199–2238; (d)
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2258.
(minor), 11.3 (major)); [
a
]
þ13.7 (c 1.15, EtOAc); [
a
]
þ11.1 (c
D
1.00, CHCl3) (lit.16 þ8.5); 1H NMR (CDCl3, 300 MHz):
d
7.43 (d,
J¼8.4 Hz, 2H), 7.38–7.24 (m, 10H), 7.18 (d, J¼8.4 Hz, 2H), 5.63 (s,
1H), 5.40–5.07 (m, 6H), 4.21–3.98 (m, 2H), 3.03 (dd, J¼13.5,
9.0 Hz, 1H), 2.30 (d, J¼13.5 Hz, 1H), 2.10 (s, 3H), 1.13 (t, J¼7.2 Hz,
3H).
4.4.2. Synthesis of 1,2-dibenzyloxycarbony-3-ethoxycarbonyl-3-
acetyl-5-(10-(400-bromophenyl)ethenyl)pyrazolidine (3S,5S)-4dg
from the reaction of (S)-3dg with MeMgBr
Under an argon atmosphere, (S)-3dg (69 mg, 0.10 mmol) and
3 mL of Et2O were added into a Schlenk tube, then MeMgBr (38 mL,
0.11 mmol, 3.0 M in diethyl ether) was added to the solution at
ꢂ78 ꢀC. The resulting solution was stirred at this temperature for
3.5 h as monitored by TLC, then it was quenched by 3 M HCl at
ꢂ78 ꢀC. After warming up to rt, the mixture was extracted with
20 mL of diethyl ether, and the organic layer was washed sequen-
tially with water and brine, and dried over sodium sulfate. Filtration
and chromatography on silica gel (eluent: petroleum ether/ethyl
acetate¼5:1) afforded 20 mg of (3S,5S)-4dg (30%); 88% ee (de-
8. For most recent reviews, see: (a) Krause, N.; Hashmi, A. S. K. Modern Allene
Chemistry; Wiley-VCH: Weinheim, Germany, 2004; Vols. 1–2; (b) Ma, S. Chem.
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Asymmetry 1994, 5, 573–584; (f) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994,
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termined by HPLC analysis (Chiralcel OD, 2% i-PrOH in hexane,
20
0.7 mL/min, 230 nm), tR 21.6 (minor), 23.3 (major)); [
a]
ꢂ41.2 (c
D
20
1.0, EtOAc); [
a]
ꢂ41.0 (c 0.85, CHCl3); 1H NMR (300 MHz, CDCl3):
D
d
7.42 (d, J¼8.4 Hz, 2H), 7.40–7.20 (m, 10H), 7.17 (d, J¼8.4 Hz, 2H),
5.63 (s, 1H), 5.36 (m, 1H), 5.31–5.05 (m, 5H), 4.13–3.95 (m, 2H), 3.26
(dd, J¼13.5, 9.6 Hz, 1H), 2.35 (s, 3H), 2.21 (dd, J¼13.5, 3.3 Hz, 1H),
1.10 (t, J¼7.5 Hz, 3H).
11. (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 815–816; (b) Trost, B. M.;
Brennan, M. K. Org. Lett. 2007, 9, 3961–3964.
Acknowledgements
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Financial supports from National Natural Science Foundation of
China (20429201 and 20732005), State Basic and Research De-
velopment Program (Grant No. 2006CB806105), and Chinese
Academy of Sciences are greatly appreciated. We thank Prof. Yong
Tang in this institute for helpful discussion in the synthesis and use
of trioxazoline ligands L4 and L5.
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