Highly diastereoselective palladium-catalyzed cyclizations of 3,4-allenylic hydrazines and organic halides-highly stereoselective synthesis of optically active pyrazolidine derivatives and the prediction of the stereoselectivity

Article abstract of DOI:10.1002/chem.200700620

Pyrazolidines containing two chiral centers, an interesting class of heterocyclic compounds possessing a range of biological activities, have been prepared highly diastereoselectively (up to 95:5) through asymmetric Pd(OAc)₂-catalyzed cyclizations between the easy available optically active allenylic hydrazines and organic halides in THF in the presence of (R,R)-Bn-Box (L2) as the ligand. It was observed 1) that in most cases (3R,5S)-pyrazolidines were obtained in good yields with very high enantiopurities (>99%) and high diastereoselectivities (up to 95:5) in the presence of (R,R)-Bn-Box (L2), 2) that aryl halides containing electron-donating or -withdrawing groups, heteroaryl, and 1-alkenyl iodides are all suitable substrates for this diastereoselective cyclization, 3) that the absolute configurations of the newly formed chiral centers in the pyrazolidines depend on the structure of substrate 1, and 4) that the enantioand diastereopurities of the trans-pyrazolidines are co-controlled by the chiralities of the chiral catalysts and the substrates. A model for prediction of the enantiopurities of the products and the diastereoselectivities of the reactions based on an HPLC study of the starting hydrazines and the products was established.

Full text of DOI:10.1002/chem.200700620

DOI: 10.1002/chem.200700620
Highly Diastereoselective Palladium-Catalyzed Cyclizations of 3,4-Allenylic
Hydrazines and Organic Halides—Highly Stereoselective Synthesis of
Optically Active Pyrazolidine Derivatives and the Prediction of the
Stereoselectivity
Qing Yang,[a, b] Xuefeng Jiang,[a] and Shengming Ma*[a]
Abstract: Pyrazolidines containing two
chiral centers, an interesting class of
heterocyclic compounds possessing a
range of biological activities, have been
prepared highly diastereoselectively
(up to 95:5) through asymmetric Pd-
with very high enantiopurities (>99%)
and high diastereoselectivities (up to
95:5) in the presence of (R,R)-Bn-Box
(L2), 2) that aryl halides containing
the absolute configurations of the
newly formed chiral centers in the pyr-
azolidines depend on the structure of
substrate 1, and 4) that the enantio-
and diastereopurities of the trans-pyra-
zolidines are co-controlled by the chir-
alities of the chiral catalysts and the
substrates. Amodel for prediction of
the enantiopurities of the products and
the diastereoselectivities of the reac-
tions based on an HPLC study of the
starting hydrazines and the products
was established.
electron-donating
or -withdrawing
groups, heteroaryl, and 1-alkenyl io-
dides are all suitable substrates for this
diastereoselective cyclization, 3) that
A
the easy available optically active alle-
nylic hydrazines and organic halides in
THF in the presence of (R,R)-Bn-Box
(L2) as the ligand. It was observed
1) that in most cases (3R,5S)-pyrazoli-
dines were obtained in good yields
Keywords: allenes
·
asymmetric
catalysis · heterocycles · hydrazines ·
palladium
Introduction
powerful protocols in modern synthetic organic chemistry,[3]
transition-metal-catalyzed asymmetric reactions for optically
active pyrazolidines have not been well developed.[4]
Pyrazolidines are an interesting class of heterocyclic com-
pounds with biological activities that have stimulated scien-
tists to design novel therapeutic agents with mimetic scaf-
folds.[1] One of the major challenges in these objectives is
the development of efficient methods for the stereoselective
synthesis of optically active pyrazolidines.[2] Although transi-
tion-metal-catalyzed reactions for the synthesis of heterocy-
clic compounds have been demonstrated as one of the most
Recently, we and others have developed transition-metal-
catalyzed coupling cyclization reactions between functional-
ized allenes and organic halides.[5] However, there are only a
few reports on catalytic diastereo- or enantioselective cou-
pling cyclization reaction between these building blocks to
afford optically active heterocyclic compounds. Larock et al.
reported asymmetric palladium-catalyzed hetero- and car-
boannulation of allenes using functionalized aryl and vinylic
halides with ees of up to 86%,[6] while in 2004 we reported a
method for the synthesis of pyrazolidine derivatives through
Cu- and Pd-catalyzed one-pot tandem reactions of function-
alized 2-(2’,3’-allenyl)-b-keto esters, dibenzyl azodicarboxy-
late, and organic halides with poor diastereoselectivity (cis/
trans 33:77–45:55).[7b] In this paper we report a double asym-
metric induction method[8] for highly diastereoselective syn-
theses of pyrazolidine derivatives with high enantiopurities
through asymmetric cyclizations between optically active
3,4-allenylic hydrazines and organic halides.
[a] Q. Yang, X. Jiang, Prof. Dr. S. Ma
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
Fax : (+86)021-64167510
E-mail: masm@mail.sioc.ac.cn
[b] Q. Yang
State Key Laboratory of Inorganic Synthesis
and Preparative Chemistry
Jilin University, Changchun 130012 (China)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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Chem. Eur. J. 2007, 13, 9310 – 9316

FULL PAPER
Results and Discussion
Our initial efforts started with the cyclization of optically
active allenylhydrazine 1a[7b] (Table 1) with organic halides.
Table 1. Ligand and solvent effects on Pd-catalyzed asymmetric cou-
pling—cyclization of 1a with PhI.[a]
Entry Ligand
Yield of 3aa
ee [%]
ee [%]
dr[d]
[%][b]
(3R,5S)[c]
(3R,5R)[c]
1
2
3
L1
L2
L3
L2
L2
69
81
83
83
76
99
98
98
97
99
88
85
99
90
76
87:13
95:5
57:43
86:14
93:7
the solvent, the result was similar to that seen in the reac-
tion carried in THF (entry 5, Table 1). On the basis of these
results, 1.0 equiv of 1, 1.2 equiv of 2, 0.4 equiv of Ag3PO4,
4[e]
5[f]
5 mol% of Pd(OAc)2, and 10 mol% of (R,R)-Bn-Box L2 in
A
[a] Reactions were typically conducted with 0.2 mmol of 1a, 0.4 mmol of
2a, 0.08 mmol Ag3PO4, 5 mol% Pd(OAc)2, and 10 mol% ligand in 2 mL
THF were defined as the standard conditions.
AHCTREUNG
Next, the scope of the highly diastereoselective catalytic
cyclization reactions between optically active allenylhydra-
zines and organic halides was studied under the standard
conditions (Table 2). It can be concluded: 1) that in most
cases (3R,5S)-pyrazolidines were obtained in good yields
and with very high enantiopurities (>99%) and high diaste-
reoselectivities (up to 95:5), 2) that aryl halides containing
electron-donating or -withdrawing groups can be used (en-
tries 2–5, Table 2), 3) that heteroaryl or 1-alkenyl iodides are
also suitable substrates for this diastereoselective cycliza-
tion process (entries 6 and 7, Table 2), the configuration
of the C=C bond in the 1-alkenyl iodide remained un-
changed during the reaction (entry 6, Table 2), 4) that R1
and R2 can be different alkyl groups (entries 9 and 10,
Table 2), and 5) that the reaction favors the formation of
THF in a tube with a screw cap at 808C. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis. [d] dr=trans/cis. [e] DMF was used as
solvent. [f] 1,4-Dioxane was used as solvent.
Accordingly, we screened several optically active palladium
catalysts prepared in situ from easily available chiral ligands
and Pd(OAc)2 (Table 1). In view of the fact that significantly
G
enhanced levels of enantioselectivity could be achieved in
the presence of silver salts,[6,9] we tried the use of Ag3PO4 as
the base. As shown in Table 1, the reaction in THF at 808C
in the presence of 0.4 equiv of Ag3PO4 as the base afforded
the desired products with interesting diastereoselectivities
when bisoxazoline (R,R)-L1 and Pd(OAc)2 were used as the
U
catalyst (entry 1, Table 1). To our surprise, when bisoxazo-
line (R,R)-L2 was then used as
the ligand, the desired pyrazo-
Table 2. Pd
U
A
lidine 3aa was produced with
very high enantiopurity (98%)
and in good yield (81%) and
diastereoselectivity
(95:5)
(entry 2, Table 1). The use of
BINAP ((R)-L3), however,
provided the desired heterocy-
cle 3aa with a poor diastereo-
selectivity (entry 3, Table 1).
Notably, the bulky ligand (S)-
L4 and the P-N ligands (R)-L5
and (R)-L6 were ineffective for
the cyclization reaction. It was
found that the reaction carried
out in DMF and catalyzed by
Entry
(R)-1 (% ee)
R3I (2)
Yield 3 [%][b]
ee [%][c] (3R,5S)
dr[d]
1
2
1a (98)
1a (98)
1a (98)
1a (98)
1a (98)
1a (98)
1a (98)
1a (98)
1b (98)
1c (98)
C6H5I
4-MeC6H4I
4-MeC6H4I
4-MeOC6H4I
4-MeO2CC6H4I
(E)-n-C4H9C2H2I
2-iodothiophene
4-BrC6H4I
81 (3aa)
81 (3ab)
80 (3ab)
85 (3ac)
83 (3ad)
82 (3ae)
67 (3af)
86 (3ag)
81 (3ba)
78 (3ca)
99
99
99
99
97
99
99
>95
99
99
94:6
92:8
93:7
94:6
95:5
93:7
95:5
93:7
91:9
92:8
3[e]
4
5
6
7
8
9[f]
10[f]
C6H5I
C6H5I
(R,R)-L2/Pd(OAc)2 gave the
A
product with a lower diastereo-
selectivity (entry 4, Table 1).
When 1,4-dioxane was used as
[a] Reactions were typically conducted under standard conditions. [b] Isolated yield. [c] Determined by chiral
HPLC analysis. [d] dr=trans/cis. [e] 1,4-Dioxane was used as solvent. [f] Reaction temperature: 708C.
Chem. Eur. J. 2007, 13, 9310 – 9316
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9311

S. Ma et al.
trans-pyrazolidines in the presence of (R,R)-L2/Pd
the catalyst.
In order to determine the origin of the asymmetric induc-
tion more precisely, a series of control experiments were
conducted. As discussed above, the reaction between (R)-1a
(OAc)2 as
that of the starting (R)-1a (entry 1, Table 1), which may be
easily explained by careful analysis of the HPLC results re-
lating to the preparation of 3aa from (R)-1 with 98.0% ee
and from (S)-1 with 97.6% ee: 98.87% of starting material
1—that is, pure (R)-1—was converted into 5.16% of
(3R,5R)-3aa and 93.71% of (3R,5S)-3aa, while 1.13% of
starting material 1—that is, pure (S)-1—was converted into
0.80% of (3S,5S)-3aa and 0.33% of (3S,5R)-3aa (entry 1,
Table 4), due to the mismatched situation of (S)-1 with
(R,R)-Box-Bn L2 (entry 2, Table 4). With this analysis, it is
reasonable to predict that the racemic 1 should also yield
the major isomer (3R,5S)-3aa with 42% ee and the minor
and PhI in the presence of Pd
N
N
lyst is diastereoselective (cis/trans 6:94), affording the trans-
pyrazolidine (3R,5S)-3aa with high enantiopurity (99% ee)
(Table 3, Entry 1). In contrast, when (S,S)-L2 was used,
(3R,5R)-3aa was obtained as the major product with high
enantiopurity but moderate diastereoselectivity, which may
be attributed to the mismatch situation between the sub-
strate and the ligand. On the
Table 4. Chiral HPLC analysis of different 3aa samples.[a]
other hand, when (S)-1 was
used as the substrate in the
Entry
Sample source of 3aa (% ee)
Integration of HPLC peaks for each stereoisomer of 3a
Isomers 3aa from (R)-1a [%] Isomers 3aa from (S)-1a [%]
presence of Pd
G
E
Total
G
G
Total
A
G
L2, products (3S,5S)-3aa and
(3S,5R)-3aa with inverted con-
figurations were formed in
99% ee and 92% ee, respec-
tively, though the diastereose-
1
2
(R)-1a (98)
(S)-1a (97.6)
rac-1a (0)
rac-1a (0)
(R)-1a (84)
(R)-1a (84)
98.87
1.46
50.00
49.00
92.00
93.13
5.16
0.36
2.61
2.38
4.80
4.82
93.71
1.10
47.39
46.62
87.20
88.31
1.13
98.54
50.00
51.00
8.00
0.80
60.56
30.73
32.42
4.92
0.33
37.98
19.27
18.58
3.08
3[b]
4
5[b]
6
lectivity was poor. When the
6.68
4.56
2.31
chiral ligand was changed to
(S,S)-L2, the corresponding
[a] See footnote a of Table 2. [b] Predicted by the results in entries 1 and 2 of Table 4 as follows:
trans-(3S,5R)-3aa was obtained
from (S)-1 with excellent enan-
tiopurity and highly diastereo-
selectively. From these results,
it can be concluded: 1) that
the absolute configurations of
the newly formed chiral cen-
ters in the pyrazolidines
depend on the structure of
substrate 1, and 2) that the enantio- and diastereopurities
for the pyrazolidines are co-controlled by the chirality of the
chiral catalysts and substrates.
Furthermore, after monitoring of the reaction between
(R)-1a and PhI shown in entry 1 of Table 1, it was found
that no racemization was observable for the starting materi-
al (R)-1a, the major product (3R,5S)-3aa, or the minor
product (3R,5R)-3aa.
isomer (3S,5S)-3aa with 84% ee (entry 3, Table 4). Actually,
the corresponding treatment of rac-1 by the standard proce-
dure in Table 2 did yield the major isomer (3R,5S)-3aa with
43% ee and the minor isomer (3S,5S)-3aa with 86% ee
[Eq. (1) in Table 4].
Furthermore, the reaction between (R)-1a with 84% ee
and PhI under the standard conditions afforded trans-
(3R,5S)-3aa with 95% ee as expected (Scheme 1).
However, it should be noted that the enantiopurity of the
minor product [(3R,5R)-3aa vs (3S,5S)-3aa] is lower than
Conclusions
Table 3. Correlation between the chiral substrates and the chiral catalysts.[a]
In conclusion, asymmetric pal-
ladium-catalyzed cyclizations
between the easily available
3,4-allenylic hydrazines and or-
ganic halides have been devel-
oped for the highly diastereo-
[c]
selective synthesis of highly
optically active pyrazolidines.
We have also established a
model with which the enantio-
purities of the products and
the diastereoselectivities of the
Entry
1a (98% ee)
Ligand
(R,R)-L2
(S,S)-L2
(R,R)-L2
(S,S)-L2
Yield [%][b]
ee (cis) [%][c]
ee (trans) [%]
dr[d]
1
2
3
4
(R)-1a
(R)-1a
(S)-1a
(S)-1a
G
81
81
80
85
73 (3R,5R)
97 (3R,5R)
99 (3S,5S)
85 (3S,5S)
99 (3R,5S)
90 (3R,5S)
94 (3S,5R)
99 (3S,5R)
6:94
65:35
61:39
6:94
AHCTREUNG
AHCTREUNG
AHCTREUNG
[a] See footnote [a] of Table 2. [b] Isolated yield. [c] Determined by chiral HPLC analysis. [d] dr=cis/trans.
9312
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Chem. Eur. J. 2007, 13, 9310 – 9316

Optically Active Pyrazolidine Derivatives
FULL PAPER
(MALDI): m/z: found: 517 [M+Na]+
; HRMS (MALDI): m/z: calcd for
C27H30N2O7Na+: 517.1945; found:
517.1958 [M+Na]+.
2-(N,N-Bis(benzyloxycarbonyl)hydra-
zino)-2-(buta-2,3-dienyl)-4-methyl-3-
oxopentanoic acid methyl ester [(R)-
1c]: The reaction of methyl 2-(buta-
2,3-dienyl)-4-methyl-3-oxopentanoate
(490 mg, 2.50 mmol), dibenzyl azodi-
carboxylate
3.00 mmol),
10 mol%), and (S,S)-(+)-2,2’-isopro-
(DBAD,
Cu(OTf)2
994 mg,
(90 mg,
Scheme 1. [a] The numbers in parentheses are the predicted ones based on the data presented in entries 3
and 5 in Table 4.
AHCTREUNG
pylidenebis(4-phenyl-2-oxazoline)
(88 mg, 10.6 mol%) in dry CH2Cl2 (20 mL) afforded (R)-1c (1.107 g,
90%) in 98% ee as determined by HPLC analysis (Chiralcel OD, 15%
iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 12.2 (minor), 13.5 min
(major); viscous liquid; [a]D20 =À3.0 (c=1.2, CHCl3); 1H NMR (CDCl3,
300 MHz): d=7.40–7.20 (m, 10H), 7.70–6.38 (m, 1H), 5.28–5.01 (m, 5H),
4.62 (br, 2H), 3,82–3.30 (m, 4H), 2.90–2.62 (m, 2H), 1.15–0.80 (m, 6H);
IR (neat): n˜ =3304, 2953, 1952, 1732, 1456, 1219 cmÀ1; MS (MALDI):
m/z: found: 517 [M+Na]+; HRMS (MALDI): m/z: calcd for
C27H30N2O7Na+: 517.1945; found: 517.1959 [M+Na]+.
reactions may be easily predicted. This reaction has paved
the way for asymmetric cyclizations of functionalized allenes
for asymmetric synthesis of enantiomerically enriched cyclic
compounds. Further study in this area is now in progress in
our laboratory.
All the spectral data for the known products have been published in the
Supporting Information of ref. [7b]. The diastereoisomers can be easily
separated by chromatography on silica gel.
Experimental Section
General procedure for the in situ synthesis of optically active palladium
Typical procedure for the synthesis of optically active 3,4-allenylic hydra-
zines with 2-(N,N-Bis(benzyloxycarbonyl)hydrazino)-2-(buta-2,3-dienyl)-
3-oxobutyric acid ethyl ester [(R)-1a] as an example:[7b]: Ethyl 2-(buta-
2,3-dienyl)-3-oxobutanoate (1.328 g, 7.2 mmol) and dibenzyl azodicarbox-
ylate (DBAD, 2.999 g, 9.1 mmol) were added at 08C to a solution of Cu-
catalysts from chiral ligands and Pd
N
N
(22.4 mg, 0.1 mmol) and chiral ligand (L1–L6, 0.2 mmol) in dry THF
(10 mL) was stirred at room temperature for 1 h as the catalyst for the
following reactions.
A
General procedure for synthesis of optically active pyrazolidine deriva-
phenyl-2-oxazoline) (255 mg, 0.78 mmol) in dry CH2Cl2 (60 mL), previ-
ously stirred at room temperature for 1 h. The mixture was then stirred
at this temperature for a further 4 h with monitoring by TLC. After evap-
oration, the residue was purified by flash chromatography on silica gel
(petroleum ether/ether 2:1) to afford (R)-1a (3.373 g, 97%) in 98% ee as
determined by HPLC analysis (Chiralcel AD, 25% iPrOH in hexane,
tives: The solution of catalyst in THF (1 mL), prepared from Pd(OAc)2
A
(5 mol%) and (R,R)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%), was added to a solution of (R)-1 (0.21 mmol), PhI
(50 mg, 0.24 mmol), and Ag3PO4 (34 mg, 0.08 mmol) in THF (1 mL), and
the reaction was allowed to proceed at 808C in a tube with a screw cap.
After the reaction was complete as monitored by TLC (petroleum ether/
ethyl acetate 3:1), rotary evaporation and flash chromatography on silica
0.7 mLminÀ1, 230 nm), tR
liquid; [a]D20 =+4.0 (c=1.1, CHCl3); 1H NMR (CDCl3, 300 MHz): d=
7.38–7.22 (m, 10H), 6.70–6.30 (m, 1H), 5.30–5.02 (m, 5H), 4.70–4.50 (m,
2H), 4.30–3.98 (m, 2H), 2.92–2.60 (m, 2H), 2.50–2.00 (m, 3H), 1.28–
1.02 ppm (m, 3H); IR (neat): n˜ =3309, 2982, 1956, 1731, 1221 cmÀ1; MS
(MALDI): m/z: found: 503.2 [M+Na]+; HRMS (MALDI): m/z: calcd
for C26H28N2O7Na+: 503.1789; found: 503.1794 [M+Na]+.
gel (petroleum ether/ethyl acetate 5:1) afforded
3 ((3R,5R)-3 and
(3R,5S)-3). All the known products were identified by comparison with
authentic samples prepared in this group.[7b]
3-Acetyl-1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-5-(1’-phenylethenyl)-
pyrazolidine (3aa) ((3R,5R)-3aa and (3R,5S)-3aa; entry 1, Table 2): The
solution of catalyst in THF (1 mL) prepared from Pd(OAc)2 (5 mol%)
U
2-(N,N-Bis(benzyloxycarbonyl)hydrazino)-2-(buta-2,3-dienyl)-3-oxobuty-
ric acid ethyl ester [(S)-1a]: The reaction of ethyl 2-(buta-2,3-dienyl)-3-
oxobutanoate (258 mg, 1.42 mmol), dibenzyl azodicarboxylate (DBAD,
and (R,R)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline) ((R,R)-L1,
10 mol%) was added to a solution of (R)-1a (102 mg, 0.21 mmol), PhI
(50 mg, 0.24 mmol), and Ag3PO4 (34 mg, 0.08 mmol) in THF (1 mL). The
reaction afforded 3aa[7] (96 mg, 81%) ((3R,5R)-3aa/3R,5S)-3aa 6:94 as
determined by HPLC analysis).
663 mg, 2.0 mmol), Cu(OTf)2 (53 mg, 10 mol%), and (R,R)-(+)-2,2’-iso-
A
propylidenebis-(4-phenyl-2-oxazoline) (54 mg, 10.4 mol%) in dry CH2Cl2
(12 mL) afforded (S)-1a (627 mg, 92%) of 97.6% ee as determined by
Isomer (3R,5R)-3aa: 73% ee as determined by HPLC analysis (Chiralcel
HPLC analysis (Chiralcel AD, 25% iPrOH in hexane, 0.7 mLminÀ1
,
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
= 13.4 (minor),
230 nm), tR = 37.3 (minor), 45.7 min (major); viscous liquid; [a]D20 =À3.0
(c=0.92, CHCl3); 1H NMR (CDCl3, 300 MHz): d=7.38–7.22 (m, 10H),
6.88–6.60 (m, 1H), 5.30–5.01 (m, 5H), 4.68–4.50 (m, 2H), 4.26–3.98 (m,
2H), 2.92–2.60 (m, 2H), 2.50–1.90 (m, 3H), 1.29–0.98 ppm (m, 3H).
17.6 min (major).
Isomer (3R,5S)-3aa: 99% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
= 22.2 (major),
30.5 min (minor).
2-(N,N-Bis(benzyloxycarbonyl)hydrazino)-2-(buta-2,3-dienyl)-3-oxo-hexa-
noic acid methyl ester [(R)-1b]: The reaction of methyl 2-(buta-2,3-
dienyl)-3-oxohexanoate (409 mg, 2.09 mmol), dibenzyl azodicarboxylate
3-Acetyl-1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-5-(1’-(4’’-methylphe-
nyl)ethenyl)pyrazolidine (3ab) ((3R,5R)-3ab and (3R,5S)-3ab) (entries 2
and 3, Table 2): The solution of catalyst in THF (1 mL) prepared from
(DBAD, 884 mg, 2.67 mmol), Cu(OTf)2 (76 mg, 10 mol%), and (S,S)-
A
Pd(OAc)2 (5 mol%) and (R,R)-(+)-2,2’-isopropylidenebis-(4-benzyl-2-ox-
R
(+)-2,2’-isopropylidenebis(4-phenyl-2-oxazoline) (73 mg, 10.4 mol%) in
dry CH2Cl2 (20 mL) afforded (R)-1b (808 mg, 78%) of 98% ee as deter-
mined by HPLC analysis (Chiralcel AD, 25% iPrOH in hexane,
azoline) ((R,R)-L1, 10 mol) was added to a solution of (R)-1a (91 mg,
0.19 mmol), 4-iodotoluene (55 mg, 0.25 mmol), and Ag3PO4 (34 mg,
0.08 mmol) in THF (1 mL). The reaction afforded 3ab[7] (87 mg, 81%)
0.7 mLminÀ1, 230 nm), tR
= 47.9 (major), 55.0 min (minor); viscous
liquid; [a]D20 =+2.4 (c=1.0, CHCl3); 1H NMR (CDCl3, 300 MHz): d=
7.40–7.22 (m, 10H), 6.85–6.60 (m, 1H), 5.30–5.05 (m, 5H), 4.63 (br, 2H),
3.80–3.50 (m, 3H), 2.90–2.50 (m, 4H), 1.80–1.40 (m, 2H), 0.88 ppm (br,
((3R,5R)-3ab/(3R,5S)-3ab 8:92 as determined by HPLC analysis).
R
Isomer (3R,5R)-3ab: 85% ee as determined by HPLC analysis (Chiralcel
AD, 10% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 25.9 (minor),
28.6 min (major).
3H); IR (neat): n˜ =3311, 2960, 1956, 1743, 1218, 1028 cmÀ1
; MS
Chem. Eur. J. 2007, 13, 9310 – 9316
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9313

S. Ma et al.
Isomer (3R,5S)-3ab: 99% ee as determined by HPLC analysis (Chiralcel
AD, 10% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 41.0 (minor),
43.8 min (major).
Isomer (3R,5R)-3af: 79% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
= 17.1 (minor),
20.3 min (major).
The solution of catalyst prepared from Pd
(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline) ((R,R)-L1, 10 mol%) in
1,4-dioxane (1 mL) was added to solution of (R)-1a (96 mg,
A
Isomer (3R,5S)-3af: 99% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
= 33.9 (minor),
a
44.8 min (major).
0.20 mmol), 4-iodotoluene (54 mg, 0.25 mmol), and Ag3PO4 (34 mg,
0.08 mmol) in 1,4-dioxane (1 mL). The reaction afforded 3ab (91 mg,
3-Acetyl-1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-5-(1’-(4’’-bromo-phe-
nyl)ethenyl)pyrazolidine (3ah) ((3R,5R)-3ah and (3R,5S)-3ah) (entry 8,
80%) ((3R,5R)-3ab/(3R,5)-3ab 7:93 as determined by HPLC analysis).
G
Table 2): The solution of catalyst prepared from Pd
ACHTREUNG
Isomer (3R,5R)-3ab: 80% ee as determined by HPLC analysis (Chiralcel
AD, 10% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 26.4 (minor),
29.1 min (major).
(R,R)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline)
10 mol%) in THF (1 mL) was added to a solution of (R)-1a (99 mg,
0.21 mmol), 1-bromo-4-iodobenzene (70 mg, 0.25 mmol), and Ag3PO4
(34 mg, 0.08 mmol) in THF (1 mL). The reaction afforded 3af[7] (112 mg,
Isomer (3R,5S)-3ab: 99% ee as determined by HPLC analysis (Chiralcel
AD, 10% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 41.3 (major),
43.9 min (minor).
86%) ((3R,5R)-3af/(3R,5S)-3ah 7:93 as determined by HPLC analysis).
N
Isomer (3R,5R)-3ah: 85% ee as determined by HPLC analysis (Chiralcel
AD, 15% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 37.4 (major),
41.2 min (minor).
3-Acetyl-1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-5-(1’-(4’’-methoxy-
phenyl)ethenyl)pyrazolidine (3ac) ((3R,5R)-3ac and (3R,5S)-3ac;
Isomer (3R,5S)-3ah: >95% ee as determined by HPLC analysis (Chiral-
Entry 4, Table 2): The solution of catalyst prepared from Pd(OAc)2
G
cel OD, 15% iPrOH in hexane, 0.7 mLminÀ1
, 230 nm), tR = 15.1
(5 mol%) and (R,R)-(+)-2,2’-isopropylidene-bis(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%) in THF (1 mL) was added to a solution of (R)-1a
(94 mg, 0.20 mmol), 4-iodoanisole (58 mg, 0.25 mmol), and Ag3PO4
(34 mg, 0.08 mmol) in THF (1 mL). The reaction afforded 3ac[7] (97 mg,
(minor), 17.1 min (major).
1,2-Dibenzyloxycarbonyl-3-butyryl-3-methoxycarbonyl-5-(1’-phenyl-ethe-
nyl)pyrazolidine (3ba) ((3R,5R)-3ba and (3R,5S)-3ba) (entry 9, Table 2):
85%) ((3R,5R)-1ac/(3R,5S)-3ac 6:94 as determined by HPLC analysis).
N
The solution of catalyst prepared from Pd(OAc)2 (5 mol%) and (R,R)-
G
(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline) ((R,R)-L1, 10 mol%) in
THF (1 mL) was added to a solution of (R)-1b (99 mg, 0.20 mmol), PhI
(55 mg, 0.26 mmol), and Ag3PO4 (34 mg, 0.08 mmol) in THF (1 mL). The
Isomer (3R,5R)-3ac: 85% ee as determined by HPLC analysis (Chiralcel
AD, 15% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 28.1 (minor),
32.1 min (major).
reaction afforded 3ba (96 mg, 81%) ((3R,5R)-3ba/(3R,5S)-3ba 9:91 as
determined by HPLC analysis).
N
Isomer (3R,5S)-3ac: 99% ee as determined by HPLC analysis (Chiralcel
AD, 15% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 40.7 (major),
48.5 min (minor).
Isomer (3R,5R)-3ba: 83% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 28.1 (minor),
33.6 (major); viscous liquid; [a]D20 =+22.0 (c=0.2, CHCl3); 1H NMR
(CDCl3, 300 MHz): d=7.39–7.22 (m, 15H), 5.62 (s, 1H), 5.42 (d, J=
8.10 Hz, 1H), 5.33–5.05 (m, 5H), 3.56 (s, 3H), 3.20 (dd, J=13.50,
9.30 Hz, 1H), 2.90–2.60 (m, 2H), 2.29 (dd, J=13.50, 3.30 Hz, 1H), 1.60–
1.35 (m, 2H), 0.76 ppm (t, J=7.35 Hz, 3H); 13C NMR (CDCl3,
75.4 MHz): d=204.3, 167.5, 156.6, 153.9, 144.7, 138.8, 135.3, 135.1, 128.6,
128.50, 128.47, 128.45, 128.39, 128. 2, 128.0, 127.9, 126.7, 113.2, 75.6, 68.8,
68.6, 62.0, 52.8, 40.2, 39.1, 16.8, 13.3 ppm; IR (neat): n˜ =3033, 2961, 1725,
3-Acetyl-1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-5-(1’-(4’’-methoxycar-
bonylphenyl)ethenyl)pyrazolidine (3ad) ((3R,5R)-3ad and (3R,5S)-3ad)
(entry 5, Table 2): The solution of catalyst prepared from Pd(OAc)2
G
(5 mol%) and (R,R)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%) in THF (1 mL) was added to a solution of (R)-1a
(98 mg, 0.20 mmol), 4-iodobenzoic acid methyl ester (64 mg, 0.24 mmol),
and Ag3PO4 (34 mg, 0.08 mmol) in THF (1 mL). The reaction afforded
3ad[7] (101 mg, (81%) ((3R,5R)-3ad/
(3R,5S)-3ad 5:95 as determined by
U
HPLC analysis).
1497, 1412, 1152 cmÀ1 MS (MALDI): m/z: found: 593.4 [M+Na]+;
;
Isomer (3R,5R)-3ad: 81% ee as determined by HPLC analysis (Chiralcel
AD, 15% iPrOH in hexane, 1 mLminÀ1, 230 nm), tR = 28.3 (minor),
34.1 min (major).
HRMS (MALDI): m/z: calcd for C33H34N2O7Na: 593.2258; found:
593.2280 [M+Na]+.
Isomer (3R,5S)-3ba: 99% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 37.2 (major),
42.5 min (minor); viscous liquid; 1H NMR (CDCl3, 300 MHz): d=7.39–
7.22 (m, 15H), 5.63 (s, 1H), 5.46 (d, J=6.90 Hz, 1H), 5.34–5.06 (m, 5H),
3.58 (s, 3H), 3.11 (dd, J=13.80, 9.60 Hz, 1H), 2.46–2.14 (m, 3H), 1.60–
1.41 (m, 2H), 0.78 ppm (t, J=7.35 Hz, 3H); 13C NMR (CDCl3,
75.4 MHz): d=199.2, 169.7, 157.0, 153.4, 144.6, 138.3, 135.42, 135.37,
128.6, 128.5, 128.4, 128.3, 128.24, 128.21, 128.1, 127.8, 126.6, 113.4, 76.9,
68.6, 68.4, 61.4, 53.1, 39.97, 39.94, 17.3, 13.5 ; IR (neat): n˜ =3033, 2962,
1725, 1498, 1412, 1151 cmÀ1; MS (MALDI): m/z: found: 593.4 [M+Na]+;
HRMS (MALDI): m/z: calcd for C33H34N2O7Na+: 593.2258; found:
593.2280 [M+Na]+.
Isomer (3R,5S)-3ad: 97% ee as determined by HPLC analysis (Chiralcel
AD, 15% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 38.9 (major),
55.9 min (minor).
3-Acetyl-1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-5-((E)-1’-methylene-
hept-2’enyl)pyrazolidine (3ae) ((3R,5R)-3ae and (3R,5S)-3ae) (entry 6,
Table 2): The solution of catalyst prepared from Pd
ACHTREUNG
(R,R)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline)
10 mol%) in THF (1 mL) was added to a solution of (R)-1a (94 mg,
0.20 mmol), (E)-1-iodohex-1-ene (56 mg, 0.26 mmol), and Ag3PO4
(34 mg, 0.08 mmol) in THF (1 mL). The reaction afforded 3ae[7] (90 mg,
82%) ((3R,5R)-3ae/(3R,5S)-3ae 7:93 as determined by HPLC analysis).
G
Isomer (3R,5R)-3ae: 83% ee as determined by HPLC analysis (Chiralcel
AD, 5 % iPrOH in hexane, 0.8 mLminÀ1, 230 nm), tR = 20.3 (minor),
21.5 min (major).
1,2-Dibenzyloxycarbonyl-3-isobutyryl-3-methoxycarbonyl-5-(1’-phenyl-
ethenyl)pyrazolidine (3ca) ((3R,5R)-3ca and (3R,5S)-3ca) (entry 10,
Table 2): The solution of catalyst prepared from Pd
ACHTREUNG
Isomer (3R,5S)-3ae: 99% ee as determined by HPLC analysis (Chiralcel
AD, 5 % iPrOH in hexane, 0.8 mLminÀ1, 230 nm), tR = 29.2 (major),
35.0 min (minor).
(R,R)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline)
10 mol%) in THF (1 mL) was added to a solution of (R)-1c (98 mg,
0.20 mmol), PhI (55 mg, 0.26 mmol), and Ag3PO4 (34 mg, 0.08 mmol) in
THF (1 mL). The reaction afforded 3ca (90 mg, 78%) ((3R,5R)-3ca/
(3R,5S)-3ca 8:92 as determined by HPLC analysis).
ACHTUNG-
3-Acetyl-1,2-dibenzyloxycarbonyl-3-ethoxycarbonyl-5-(1’-(2’’-thienyl)-
ethenyl)pyrazolidine (3af) ((3R,5R)-3af and (3R,5S)-3af) (entry 7,
TERUNG
Table 2): The solution of catalyst prepared from Pd
(R,R)-(+)-2,2’-isopropylidenebis-(4-benzyl-2-oxazoline)
10 mol%) in THF (1 mL) was added to a solution of (R)-1a (101 mg,
0.21 mmol), 2-iodothiophene (53 mg, 0.25 mmol), and Ag3PO4 (34 mg,
0.08 mmol) in THF (1 mL). The reaction afforded 3af[7] (78 mg, 66%)
A
Isomer (3R,5R)-3ca: 81% ee as determined by HPLC analysis (Chiralcel
OD, 3% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 16.4 (major),
18.0 min (minor); viscous liquid; [a]D20 =+55.0 (c=0.2, CHCl3); 1H NMR
(CDCl3, 300 MHz): d=7.35–7.18 (m, 15H), 5.57 (d, J=1.20 Hz, 1H),
5.41 (dd, J=8.55, 1.35 Hz, 1H), 5.25–5.01 (m, 5H), 3.49 (s, 3H), 3.27–
3.17 (m, 1H), 3.08 (dd, J=13.50, 9.00 Hz, 1H), 2.24 (dd, J=13.50,
((3R,5R)-3af/(3R,5S)-3af 5:95 as determined by HPLC analysis).
A
9314
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9310 – 9316

Optically Active Pyrazolidine Derivatives
FULL PAPER
2.40 Hz, 1H), 0.98 (d, J=6.60 Hz, 3H), 0.87 ppm (d, J=6.60 Hz, 3H);
13C NMR (CDCl3, 75.4 MHz): d=208.2, 167.8, 156.2, 154.4, 144.2, 138.7,
135.25, 135.22, 128.50, 128.47, 128.43, 128.35, 128.33, 128.30, 128.0, 127.9,
126.6, 113.6, 76.0, 68.68, 68.64, 61.5, 52.6, 38.9, 36.3, 20.6, 20.3 ppm; IR
Isomer (3S,5R)-3aa: 86% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
=
20.9 (major),
28.5 min (minor).
Entry 6, Table 4: Asolution of catalyst prepared from Pd
ACHTREUNG
(neat): n˜ =3032, 2954, 1741, 1716, 1497, 1456, 1002, 698 cmÀ1
; MS
(5 mol%) and (R,R)-(+)-2,2’-isopropylidenebis-(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%) in THF (1 mL) was added to a solution of (R)-1a
(84% ee) (95 mg, 0.20 mmol), PhI (84 mg, 0.4 mmol), and Ag3PO4
(33 mg, 0.08 mmol) in THF (1 mL). The reaction afforded 3aa (93 mg,
(MALDI): m/z: found: 571.2 [M+H]+; HRMS (MALDI): m/z: calcd for
C33H34N2O7Na+: 593.2258; found: 593.2272 [M+Na]+.
Isomer (3R,5S)-3ca: 99% ee as determined by HPLC analysis (Chiralcel
OD, 3% iPrOH in hexane, 0.7 mLminÀ1, 230 nm), tR = 21.2 (minor),
32.2 min (major); viscous liquid; [a]D20 =+19.9 (c=3.5, CHCl3); 1H NMR
(CDCl3, 300 MHz): d=7.40–7.25 (m, 15H), 5.64 (s, 1H), 5.45 (d, J=
7.20 Hz, 1H), 5.35–5.02 (m, 5H), 3.56 (s, 3H), 3.09 (dd, J=13.50,
9.00 Hz, 1H), 2.84–2.74 (m, 1H), 2.36 (d, J=13.50, 1H), 0.99 (d, J=
6.60 Hz, 3H), 0.90 ppm (d, J=6.60 Hz, 3H); 13C NMR (CDCl3,
75.4 MHz): d=203.8, 169.9, 157.0, 153.6, 144.1, 138.4, 135.5, 135.4, 128.5,
128.3, 128.16, 128.13, 128.09, 127.9, 127.7, 126.7, 113.5, 76.7, 68.5, 68.2,
61.2, 53.0, 40.2, 37.5, 20.3, 20.0 ppm; IR (neat): n˜ =3033, 2952, 1716, 1498,
1455, 1395, 1338, 1154, 698 cmÀ1; MS (MALDI): m/z: found: 571.2
[M+H]+; HRMS (MALDI): m/z: calcd for C33H34N2O7Na+: 593.2258;
found: 593.2271 [M+Na]+.
85%) ((3R,5R)-3aa/(3R,5S)-3aa 9:91 as determined by HPLC analysis).
G
Isomer (3R,5R)-3aa: 2.7% ee as determined by HPLC analysis (Chiral-
cel AD, 5% iPrOH in hexane, 1 mLminÀ1, 230 nm), tR = 19.2 (minor),
25.7 min (major).
Isomer (3R,5S)-3aa: 95% ee as determined by HPLC analysis (Chiralcel
AD, 5 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
= 34.3 (major),
46.5 min (minor).
Acknowledgements
Correlation between the chiral substrates and the chiral catalysts
Entry 2, Table 3: Asolution of catalyst prepared from Pd (OAc)2
A
Financial support from the National Natural Science Foundation of
China (20121202, 20332060, and 20423001) and Shanghai Municipal
Committee of Science and Technology is greatly appreciated. We thank
Mr. Zhiqiang Liang for reproducing the results presented in entries 1, 5,
7, and 8 of Table 2.
(5 mol%) and (S,S)-(+)-2,2’-isopropylidenebis-(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%) in THF (1 mL) was added to a solution of (R)-1a
(96 mg, 0.20 mmol), PhI (50 mg, 0.24 mmol), and Ag3PO4 (33 mg,
0.08 mmol) in THF (1 mL). The reaction afforded 3aa (90 mg, 81%)
((3R,5R)-3aa/(3R,5S)-3aa 65:35 as determined by HPLC analysis).
A
Isomer (3R,5R)-3aa: 97% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
16.1min (major).
= 12.1 (minor),
[1] a) V. V. Khau, M. J. Martinelli, Tetrahedron Lett. 1996, 37, 4323; b) S.
Hanessian, G. McNaughton-Smith, H.-G. Lombart, Tetrahedron 1997,
53, 12789; c) H.-O. Kim, C. Lum, M. S. Lee, Tetrahedron Lett. 1997,
38, 4935; d) K. M. K. Kutterer, J. M. Davis, G. Singh, Y. Yang, W. Hu,
A. Severin, B. A. Rasmussen, G. Krishnamurthy, A. Faillic, A. H.
Katzc, Bioorg. Med. Chem. Lett. 2005, 15, 2527; e) J. H. Ahn, J. A.
Kim, H.-M. Kim, H.-M. Kwon, S.-C. Huh, S. D. Rhee, K. D. Kim, S.-
D. Yang, S.-D. Park, J. M. Lee, S. S. Kim, H. G. Cheon, Bioorg. Med.
Chem. Lett. 2005, 15, 1337; f) H. G. Cheon, S.-S. Kim, K.-R. Kim, S.-
D. Rhee, S.-D. Yang, J. H. , J. H. Ahn, S.-D. Park, J. M. Lee, W. H.
Jung, H. S. Lee, H. Y. Kim, Biochem. Pharmacol. 2005, 70, 22.
[2] For recent reports on synthesis of optically active pyrazolidines, see:
a) F. M. Guerra, M. R. Mish, E. M. Carreira, Org. Lett. 2000, 2, 4265;
b) G. A. Whitlock, E. M. Carreira, Helv. Chim. Acta 2000, 83, 2007;
c) J. Barluenga, F. Fernandez-Mari, A. L. Viado, E. Aguilar, B.
Olano, S. Garcia-Granda, C. Moya-Rubiera, Chem. Eur. J. 1999, 5,
883; d) B. Stanovnik, B. Jelen, C. Turk, M. Zlicar, J. Svete, J. Hetero-
cycl. Chem. 1998, 35, 1187; e) M. R. Mish, F. M. Guerra, E. M. Car-
reira, J. Am. Chem. Soc. 1997, 119, 8379; f) F. P. J. T. Rutjes, N. M.
Teerhuis, H. Hiemstra, W. N. Speckhamp, Tetrahedron 1993, 49, 8605;
g) J. K. Gallos, A. E. Koumbis, N. E. Apostolakis, J. Chem. Soc.
Perkin Trans. 1 1997, 2457; h) A. Chauveau, T. Martens, M. Bonin, L.
Micouin, H.-P. Husson, Synthesis 2002, 1885.
Isomer (3R,5S)-3aa: 90% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
=
20.0 (major),
27.5 min (minor).
Entry 3, Table 3: Asolution of catalyst prepared from Pd
ACHTREUNG
(5 mol%) and (R,R)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%) in THF (1 mL) was added to a solution of (S)-1a
(98 mg, 0.20 mmol), PhI (50 mg, 0.24 mmol), and Ag3PO4 (34 mg,
0.08 mmol) in THF (1 mL). The reaction afforded 3aa (91 mg, 80%)
((3S,5S)-3aa/(3S,5R)-3aa 61:39 as determined by HPLC analysis).
R
Isomer (3S,5S)-3aa: 99% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
= 12.1 (major),
16.2 min (minor).
Isomer (3S,5R)-3aa: 94% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
=
19.9 (minor),
27.3 min (major).
Entry 4, Table 3: Asolution of catalyst prepared from Pd
ACHTREUNG
(5 mol%) and (S,S)-(+)-2,2’-isopropylidenebis(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%) in THF (1 mL) was added to a solution of (S)-1a
(96 mg, 0.20 mmol), PhI (50 mg, 0.24 mmol), and Ag3PO4 (34 mg,
0.08 mmol) in THF (1 mL). The reaction afforded 3aa (95 mg, 85%)
((3S,5S)-3aa/(3S,5R)-3aa 6:94 as determined by HPLC analysis).
N
[3] For recent reviews on transition metal-catalyzed reactions for synthe-
sis heterocyclic compounds, see: a) J. Royer, M. Bonin, L. Micouin,
Chem. Rev. 2004, 104, 2285; b) I. Nakamura, Y. Yamamoto, Chem.
Rev. 2004, 104, 2127; c) A. Deiters, S. F. Martin, Chem. Rev. 2004,
104, 2199; d) M. D. McReynolds, J. M. Dougherty, P. R. Hanson,
Chem. Rev. 2004, 104, 2239.
[4] For recent reports on the synthesis of optically active pyrazolidines
through zirconium-catalyzed enantioselective [3+2] cycloadditions
between hydrazones and olefins, see: a) S. Kobayashi, H. Shimizu, Y.
Yamashita, H. Ishitani, J. Kobayashi, J. Am. Chem. Soc. 2002, 124,
13678; b) Y. Yamashito, S. Kobayashi, J. Am. Chem. Soc. 2004, 126,
11279.
[5] For most recent reviews, see: a) N. Krause, A. S. K. Hashmi, Modern
Allene Chemistry, Vols. 1–2, Wiley-VCH, Weinheim (Germany),
2004; b) S. Ma, Chem. Rev. 2005, 105, 2829.
[6] a) R. C. Larock, J. M. Zenner, J. Org. Chem. 1995, 60, 482; b) R. C.
Larock, J. M. Zenner, J. Org. Chem. 1999, 64, 7312.
Isomer (3S,5S)-3aa: 85% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
= 12.1 (major),
16.1 min (minor).
Isomer (3S,5R)-3aa: 99% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
=
19.9 (minor),
27.1 min (major).
Entry 4, Table 4: Asolution of catalyst prepared from Pd
ACHTREUNG
(5 mol%) and (R,R)-(+)-2,2’-isopropylidenebis-(4-benzyl-2-oxazoline)
((R,R)-L1, 10 mol%) in THF (1 mL) was added to a solution of rac-1a
(96 mg, 0.20 mmol), PhI (82 mg, 0.4 mmol), and Ag3PO4 (34 mg,
0.08 mmol) in THF (1 mL). The reaction afforded 3aa (88 mg, 79%)
((3S,5S)-3aa/(3R,5S)-3aa 35:65 as determined by HPLC analysis).
R
Isomer (3S,5S)-3aa: 43% ee as determined by HPLC analysis (Chiralcel
AD, 7 % iPrOH in hexane, 1 mLminÀ1, 230 nm), tR
=
12.5 (major),
16.7 min (minor).
Chem. Eur. J. 2007, 13, 9310 – 9316
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9315

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Received: April 24, 2007
Published online: August 15, 2007
9316
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ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9310 – 9316