Synthesis of new chiral N-heterocyclic carbenes from naturally occurring podophyllotoxin and their application to asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2006.06.003

Chiral N-heterocyclic carbenes (NHC) were synthesized from naturally occurring podophyllotoxin. Their coordination with [(η³-allyl)Pd(Br)]₂ afforded (NHC)Pd(allyl)Br complexes, whose structures were unambiguously established by X-ray

Full text of DOI:10.1016/j.tetasy.2006.06.003

Tetrahedron: Asymmetry 17 (2006) 1650–1654
Synthesis of new chiral N-heterocyclic carbenes from
naturally occurring podophyllotoxin and their application
to asymmetric allylic alkylation
Shi-Jun Li, Jian-Hua Zhong and Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
Received 10 April 2006; accepted 1 June 2006
Abstract—Chiral N-heterocyclic carbenes (NHC) were synthesized from naturally occurring podophyllotoxin. Their coordination
3
with [(g -allyl)Pd(Br)]
2
afforded (NHC)Pd(allyl)Br complexes, whose structures were unambiguously established by X-ray single crystal
analysis. These chiral NHC and NHC-Pd-allyl complexes were found to catalyze the substitution reaction of allylic compounds with
high conversions and enantioselectivities (up to 87% ee).
ꢀ
2006 Elsevier Ltd. All rights reserved.
1
. Introduction
di-NHC ligand for rhodium-catalyzed hydrosilylation of
8
ketones. Ruthenium-catalyzed asymmetric olefin metathe-
9
Over the past decade, N-heterocyclic carbenes (NHC) have
emerged as one of the most important classes of com-
pounds used as ancillary ligands for a number of late tran-
sis has also been reported.
Podophyllotoxin 1, a natural antitumor drug and a starting
material for the preparation of a class of antitumor agents
such as etoposide (VP-16), has a rigid structure and steric
hindrance, so it should be a suitable building block for
the design of chiral ligands. Additionally, this chiron is
inexpensive and readily available via extraction from Podo-
1
sition metal mediated catalytic reactions. In general, it
appears that catalytic reactions, which employ transition-
metal complexes of tertiary phosphines, may also be cata-
lyzed using complexes of NHC; many of the precatalysts
studied to date exhibit excellent thermal stability and the
1
–3
10
need for excess NHC ligand is not required.
The high
phyllum peltatum or synthesis from simple compounds.
thermal stability and good catalytic activity of metal com-
plexes are due to the strong r-donor properties of NHC
combined with poor p-acceptor ability. A range of very
active NHC catalysts have been synthesized in recent years.
The most prominent examples are the second and third
Recently, we synthesized three new palladium complexes
of chiral NHC ligands from naturally occurring podophyl-
lotoxin, and found that they could catalyze the intermole-
cular asymmetric allylic alkylation reaction. Herein we
report the primary results of this work.
4
generation Grubbs olefin metathesis catalysts as well as
several novel palladium C–C coupling catalysts for Suzuki–
5
Miyaura, Kumada and Heck-type reactions. Recently,
2. Results and discussion
the potential of NHC-based ligands for asymmetric cata-
lytic chemistry was realized and a number of chiral NHC
ligands giving high enantioselectivities were prepared.
As shown in Scheme 1, four imidazolium salts 3a–d were
designed, in which a chiral center of podophyllotoxin moi-
ety was directly attached to the N-1 of an imidazole ring. 1
was converted to mesylate 2 with mesyl chloride in the
presence of triethylamine. Treatment of 2 with the corre-
3
These include NHC-oxazoline hybrid ligands for iridium-
6
catalyzed intermolecular hydrogenation of aryl alkenes;
rhodium-catalyzed hydrosilylation of ketones,7 and a
sponding 1-substituted imidazoles in CH CN gave the cor-
3
responding imidazolium mesylate salts 3 in yields ranging
from 62% to 86%. Imidazolium salts are common precur-
sors to NHC ligands. To probe the coordination mode
*
Corresponding author. Tel./fax: +86 571 87951512; e-mail:
orgwyg@zju.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.003

S.-J. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1650–1654
1651
R
N
OH
OMs
R
N
N
CH3SO3
O
O
O
O
O
O
O
O
O
O
MsCl, Et N
N
3
O
O
CH Cl
2
3
CH CN
2
OMe
OMe
MeO
MeO
OMe
MeO
OMe
OMe
OMe
1
2: 85%
3a: 86%
3
b: 62%
c: 78%
3d: 81%
R
N
3
Pd
Br
O
N
Br
Pd Pd
Br
O
O
O
3a, 4a: R=methyl
3b, 4b: R=phenyl
KOt-Bu, THF
3
c, 4c: R=2,6-dimethyl-phenyl
4
a: 67%
OMe 4b: 78%
c: 80%
d: 85%
3d, 4d: R=2,4,6-trimethyl-phenyl
MeO
4
OMe
4
Scheme 1. Synthesis of chiral NHC precursors and their palladium complexes.
and conformations of these NHC ligands, (NHC)Pd-
unambiguously established by X-ray single-crystal diffrac-
tion analysis (Fig. 1).
1
2
(
allyl)Br complexes 4 were prepared via a reaction between
3
imidazolium salts 3 and [(g -allyl)Pd(Br)] according to a
2
1
1
published method. The structure of complex 4a was
Nolan et al. have demonstrated that mononuclear palla-
dium-allyl complexes bearing achiral NHC ligands are effi-
1
1
cient catalysts of several cross-coupling reactions. Based
on these results, we investigated the possibility of the chiral
palladium-allyl complexes 4 as a catalyst in allylic alkyl-
ation reaction. The asymmetric allylic alkylation of (E)-
1,3-diphenylprop-3-en-1-yl acetate with diethylmalonate
was used as the model reaction and the results are summa-
rized in Table 1.
Table 1. Asymmetric allylic alkylation catalyzed by 4 or [Pd]/3
COOEt
EtOOC
COOEt
COOEt
+
OAc
4
or [Pd]/ 3, KOtBu
NaH, THF
a
b
Entry
Catalyst
Yield (%)
[R] ee%
1
2
3
4
5
6
7
4a
4b
4c
4d
22
82
85
83
26
68
91
79
88
93
32
53
76
79
20
54
75
42
82
87
3a/Pd
3b/Pd
3c/Pd
3c/Pd
3c/Pd(OAc)
3d/Pd(OAc)
2
(dba)
(dba)
3
/KOtBu
/KOtBu
/KOtBu
/KOtBu
/KOtBu
2
3
2
(dba)
(dba)
3
c
8
9
2
3
2
1
0
2
/KOtBu
a
b
c
Isolated yields.
Determined by chiral HPLC (Pirkle (R,R)-whelk-O1).
3c/Pd (dba) /KOtBu and rac-E-1,3-diphenyl allyl acetate were added
together.
˚
Figure 1. Molecular structure of complex 4a. Selected bond lengths (A):
Pd(1)–C(14) = 2.048, Pd(1)–Br(1) = 2.500, Pd(1)–C(18) = 2.102, Pd(1)–
C(19) = 2.134, Pd(1)–C(20) = 2.171.
2
3

1652
S.-J. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1650–1654
As shown in Table 1, either (NHC)Pd(allyl)Br complex 4a
temperature. Most of the solvent was evaporated and ethyl
acetate (50 mL) added. The resulting precipitation was col-
lected by filtration and washed with ethyl acetate
(2 · 50 mL) to give imidazolium mesylate salts 3 as an
off-white powder.
(
entry 1) or Pd (dba) combining with NHC precursor 3a
2 3
(
entry 5) gave poor yields and enantioselectivities, while
complexes 4b, 4c, and 4d bearing a bulky substituent at
N-2 of imidazoline ring (entries 2–4) or Pd (dba) combin-
2
3
ing with imidazolium salts 3b and 3c (entries 6 and 7) gave
moderate to high yields and enantioselectivities. These
results demonstrated that the catalytic activity and enantio-
selectivity strongly depend on the substituents at the N
atom of imidazoline ring of ligands, which is similar to
1
Compound 3a: 86% yield; H NMR (500 MHz, D O): d
2
3.14–3.15 (m, 1H), 3.27 (br, 1H), 3.54 (t, J = 9.6 Hz, 1H),
3.60 (s, 3H), 3.66 (s, 6H), 3.80 (s, 3H), 4.42 (t,
J = 7.6 Hz, 1H), 4.58 (d, J = 4.6 Hz, 1H), 5.77 (s, 1H),
5.86 (s, 1H), 6.00 (d, J = 3.3 Hz, 1H), 6.25 (s, 1H), 6.33
(s, 2H), 6.72 (s, 1H), 7.39 (s, 1H), 7.47 (s, 1H), 8.52 (s,
1
1d,13
the published results.
N-2 of the imidazoline moiety of 3a or 4a with phenyl
entries 2 and 6), 2,6-dimethylphenyl (entries 3 and 7) or
,4,6-trimethylphenyl (entries 4 and 10) led to a dramatic
Replacement of the methyl at
+
(
2
1H); MS (ESI): m/z = 479 ([MÀMsO] ).
1
improvement of yield and enantioselectivity. Additionally,
Compound 3b: 62% yield; H NMR (400 MHz, D O): d
2
Pd(OAc) (entries 9 and 10) afforded a superior enantiose-
3.19–3.27 (m, 1H), 3.34–3.37 (m, 1H), 3.56 (s, 3H), 3.66
(s, 6H), 4.30 (d, J = 8.4 Hz, 1H), 4.51 (t, J = 8.4 Hz, 1H),
4.62–4.66 (m, 1H), 5.86 (s, 1H), 5.90 (s, 1H), 6.15 (d,
J = 4.8 Hz, 1H), 6.34–6.41 (m, 2H), 6.45 (br, 1H), 6.81 (s,
2
lectivity as compared with Pd (dba) (entry 6) when an
2
3
in situ catalytic procedure was adopted.
1
H), 7.49–7.62 (m, 5H), 7.79 (t, J = 1.6 Hz, 1H), 9.07 (s,
+
3. Conclusion
1H); MS (ESI): m/z = 541 ([MÀMsO] ).
1
We have prepared a new class of chiral NHC ligands and
their palladium-allyl complexes from naturally occurring
podophyllotoxin. Their application in a palladium-cata-
lyzed allylic alkylation has been studied with high conver-
sions (up to 93%) and enantioselectivities (up to 87% ee)
being obtained.
Compound 3c: 78% yield; H NMR (400 MHz, D O): d
2
1.82 (s, 3H), 1.90 (s, 3H), 3.02–3.07 (m, 1H), 3.25–3.29
(m, 1H), 3.39 (s, 3H), 3.56 (s, 6H), 4.40 (t, J = 4.4 Hz,
1H), 4.47–4.51 (m, 1H), 5.73 (s, 1H), 5.78 (s, 1H), 6.11
(br, 2H), 6.23–6.26 (m, 2H), 6.76 (s, 1H), 7.07–7.10 (m,
2H), 7.21 (t, J = 7.2 Hz, 1H), 7.55–7.58 (m, 1H), 7.65 (s,
H); MS (ESI): m/z = 569 ([MÀMsO] ).
+
1
1
4
. Experimental
Compound 3d: 81% yield; H NMR (400 MHz, D O): d
2
2.01 (s, 3H), 2.05 (s, 3H), 2.16 (br, 1H), 2.32 (s, 3H),
All reactions were carried out under a nitrogen atmosphere
using standard vacuum line techniques and glassware that
was flame dried and cooled under nitrogen before
3.05–3.09 (m, 1H), 3.35–3.39 (m, 2H), 3.73 (s, 6H), 3.79
(s, 3H), 4.74 (br, 1H), 4.98 (br, 1H), 5.99 (s, 1H), 6.00 (s,
1H), 6.28 (s, 2H), 6.59 (s, 1H), 6.86 (br, 1H), 6.99 (s,
2H), 7.13–7.17 (m, 1H), 7.30–7.33 (m, 1H), 10.90 (br,
use. DCM was dried with CaH and THF was dried with
2
+
sodium. All other solvents or reagents were used as sup-
plied (analytical or HPLC grade) without prior purification.
1H); MS (ESI): m/z = 583 ([MÀMsO] ).
4.2. General procedure for the synthesis of palladium-allyl
complexes 4
1
13
The H and C NMR spectra were recorded on a Bruc-
ker Spectrospin Avance 500 or 400 spectrometer. Chemi-
cal shifts are given in parts per million downfield from
tetramethylsilane. Mass spectra were recorded on a Bruc-
ker Esruire 3000 Plus. HPLC measurements were per-
formed with an Agilent 1100 instrument. Separations
were carried out on Pirkle (R, R) Whelk-O1 analytical
column (250 · 4.60 mm) with hexane/2-propyl alcohol as
eluent.
3
A solution of 3 (0.3 mmol), [Pd(g -C H )Br] (70 mg,
3
5
2
0.15 mmol) and potassium tert-butoxide (35 mg, 0.3 mmol)
in THF (5 mL) was stirred for 5 h at room temperature
under nitrogen. The mixture was filtered in air, and the
precipitate washed with THF (2 · 10 mL). The filtrate
was evaporated on a rotary evaporator and the residue
purified by flash chromatography on silica gel with ethyl
acetate/hexane (2:1) to give 4 as a white solid.
4
.1. General procedure for the synthesis of imidazolium salts 3
1
Compound 4a: 67% yield; H NMR (500 MHz, CDCl ): d
3
To a solution of podophyllotoxin 1 (2.07 g, 5 mmol) in
DCM (40 mL) was added triethylamine (0.84 mL, 6 mmol)
and mesyl chloride (0.48 mL, 6 mmol) at 0 ꢁC. Then the
mixture was stirred for 2 h at room temperature. After
washing with water (2 · 20 mL) and brine (1 · 20 mL),
the organic layers were dried over Na SO , concentrated
2.76 (d, J = 11.8 Hz, 1H), 2.96–3.08 (m, 2H), 3.34–3.45 (m,
2H), 3.66 (d, J = 5.0 Hz, 1H), 3.78 (s, 6H), 3.81 (s, 3H),
3.88 (s, 3H), 4.10–4.14 (m, 1H), 4.22 (d, J = 8.4 Hz, 1H),
4.38 (d, J = 7.2 Hz, 1H), 4.72 (dd, J = 5.0 Hz, 12.6 Hz,
1H), 5.25–5.30 (m, 1H), 5.97 (s, 2H), 6.30 (d,
J = 16.1 Hz, 2H), 6.52–6.58 (m, 2H), 6.95 (s, 1H), 7.20 (s,
2
4
1
3
under reduced pressure, and crystallized from ethyl ace-
1H); C NMR (125 MHz, CDCl ): d 37.2, 38.7, 41.7,
3
tate/hexane to afford 2.1 g (85%) of 2. Mesylate 2 (0.99 g,
43.9, 52.1, 52.5, 56.5, 57.5, 57.9, 60.9, 68.2, 68.6, 73.0,
101.9, 108.3, 109.9, 110.2, 114.8, 115.5, 121.1, 122.7,
126.9, 132.6, 134.6, 148.2, 149.2, 153.0, 173.7, 181.5; MS
(ESI): m/z = 625 ([MÀBr] ).
2
mmol) and 1-substituted imidazole (6 mmol) were
dissolved in CH CN (10 mL). The resulting solution was
3
+
stirred at 80 ꢁC for 24 h, and then cooled to room

S.-J. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1650–1654
1653
1
Compound 4b: 78% yield; H NMR (400 MHz, CDCl ): d
After cooling to room temperature, aqueous saturated
3
1
(
4
.50 (d, J = 12.4 Hz, 1H), 2.94–3.00 (m, 2H), 3.02–3.13
m, 2H), 3.32–3.37 (m, 1H), 3.70 (s, 6H), 3.74 (s, 3H),
.14–4.18 (m, 2H), 4.36 (t, J = 8.0, 1H), 4.68 (d,
J = 5.0 Hz, 1H), 5.00–5.10 (m, 1H), 5.90 (d, J = 4.4 Hz,
NH Cl solution (10 mL) was added, and the reaction
4
mixture extracted with Et O (3 · 10 mL). The combined
2
organic layers were dried over Na SO , concentrated under
2
4
reduced pressure, and the residue purified by flash chroma-
tography on silica gel with ethyl acetate/hexane (1:30).
2
6
3
H), 6.24 (s, 2H), 6.51 (s, 1H), 6.60 (d, J = 1.6 Hz, 1H),
.78 (d, J = 4.4 Hz, 1H), 7.17–7.18 (m, 1H), 7.35–7.45 (m,
After evaporation of the solvent under reduced pressure
1
3
1
H), 7.7 (s, 1H), 7.8 (s, 1H); C NMR (100 MHz, CDCl3):
the pure product was obtained as a colorless oil.
H
d 36.9, 40.4, 41.3, 43.7, 53.8, 56.1, 56.2, 57.5, 60.7, 66.3, 67.7,
NMR (500 MHz, CDCl ): d 1.01 (t, J = 7.1 Hz, 3H), 1.22
3
7
1
1
1.1, 101.6, 107.8, 108.0, 110.1, 113.8, 118.2, 121.4, 124.8,
(t, J = 7.1 Hz, 3H), 3.92 (d, J = 11.0 Hz, 1H), 3.97 (dd,
J = 2.5 Hz, 7.1 Hz, 2H), 4.17 (dd, J = 2.5 Hz, 7.1 Hz,
2H), 4.26 (dd, J = 8.6 Hz, 11.0 Hz, 1H), 6.32 (dd,
J = 8.6 Hz, 15.8 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 7.19–
27.4, 129.1, 129.8, 130.4, 132.3, 134.4, 137.2, 147.2, 149.0,
+
52.4, 152.7, 173.4, 182.0; MS (ESI): m/z = 687 ([MÀBr] ).
1
+
Compound 4c: 80% yield; HNMR (400 MHz, CDCl ): d
7.31 (m, 10H); MS (ESI): m/z = 375 ([M+Na] ).
3
1.57 (d, J = 12.4 Hz, 1H), 1.98 (s, 3H), 2.14–2.16 (m,
1H), 2.32 (s, 3H), 2.83–3.00 (m, 2H), 3.03–3.08 (m, 1H),
3.30–3.35 (m, 1H), 3.69 (s, 3H), 3.73 (s, 6H), 4.10 (dd,
Acknowledgments
J = 1.2 Hz, 7.2 Hz, 1H), 4.17 (dd, J = 7.6 Hz, 8.4 Hz,
1
2
H), 4.60–4.72 (m, 2H), 4.96–5.07 (m, 1H), 5.89–5.93 (m,
H), 6.25 (s, 1H), 6.42 (s, 1H), 6.50–6.55 (m, 1H), 6.63
The authors would like to thank the Natural Science
Foundation of Zhejiang Province (R404109), the Special-
ized Research Fund for Doctoral Program of Higher
Education, China (20050335101), and the Teaching and
Research Award Program for Outstanding Young Teach-
ers in Higher Education Institutions of MOE, PR China.
(
d, J = 1.6 Hz, 1H), 6.91–6.93 (m, 1H), 7.06–7.13 (m,
1
3
2
H), 7.17–7.23 (m, 1H), 7.40 (s, 1H);
C NMR
(
100 MHz, CDCl ): d 17.8, 19.0, 36.9, 41.3, 43.6, 45.6,
3
5
1
1
1
3.0, 56.1, 56.2, 56.9, 60.5, 67.8, 69.8, 72.4, 101.2, 107.8,
08.0, 110.0, 114.2, 117.9, 121.0, 126.5, 127.6, 128.7,
29.3, 132.3, 134.3, 135.3, 136.5, 138.2, 147.9, 148.8,
52.6, 173.3, 182.6; MS (ESI): m/z = 715 ([MÀBr] ).
+
References
1
Compound 4d: 85% yield; HNMR (400 MHz, CDCl ): d
3
1. Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
1
1
3
3
.68 (d, J = 12.4 Hz, 1H), 1.99 (s, 3H), 2.13–2.16 (m,
H), 2.31 (s, 3H), 2.33 (s, 3H), 2.91 (d, J = 13.2 Hz, 1H),
.02 (dd, J = 4.8 Hz, 14.4 Hz, 1H), 3.08–3.12 (m, 1H),
.35–3.45 (m, 2H), 3.75 (s, 6H), 3.79 (s, 3H), 4.16–4.18
2
. Perry, M. C.; Burgess, K. Tetrahedron: Asymmetry 2003, 14,
951.
3. C e´ sar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Chem. Soc.
Rev. 2004, 33, 619.
4
. (a) F u¨ rstner, A.; Ackermann, L.; Gabor, B.; Goddard, R.;
Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chem.
Eur. J. 2001, 7, 3236; (b) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18; (c) Ung, T.; Hejl, A.; Grubbs, R. H.;
Schrodi, Y. Organometallics 2004, 23, 5399.
(m, 1H), 4.22 (dd, J = 7.2 Hz, 8.8 Hz, 1H), 4.72 (d,
J = 5.2 Hz, 1H), 5.02–5.12 (m, 1H), 5.97 (s, 2H), 6.30 (s,
1
H), 6.47 (br, 1H), 6.56–6.60 (m, 1H), 6.66 (d,
1
3
J = 1.6 Hz, 1H), 6.91–6.99 (m, 3H), 7.45 (s, 1H);
NMR (100 MHz, CDCl ): d 17.6, 17.7, 21.0, 36.6, 41.4,
C
3
5
. (a) Gstottmayr, C. W. K.; Bohm, V. P. W.; Herdtweck, E.;
Grosche, M.; Herrmann, W. A. Angew. Chem., Int. Ed. 2002,
4
1
1
1
3.7, 56.3, 56.6, 58.5, 60.6, 68.1, 77.2, 102.0, 108.0, 109.0,
10.4, 122.2, 123.4, 123.8, 129.9, 130.0, 130.4, 133.7,
33.8, 133.9, 137.5, 139.4, 141.6, 148.3, 149.7, 152.8,
52.9, 172.9; MS (ESI): m/z = 729 ([MÀBr] ).
4
1, 1363; (b) Wang, A.-E.; Zhong, J.; Xie, J.-H.; Li, K.; Zhou,
Q.-L. Adv. Synth. Catal. 2004, 346, 595; (c) Singh, R.; Mihai,
S. V.; Natalia, K.; Navarro, O.; Nolan, S. P. Org. Lett. 2005,
+
7
, 1829; (d) Arentsen, K.; Caddick, S.; Cloke, F. G. N.;
Herring, A. P.; Hitchcock, P. B. Tetrahedron Lett. 2004, 45,
511.
4
.3. Typical procedures for asymmetric allylic alkylation
3
6
7
. (a) Powell, M. T.; Hou, D. R.; Perry, M. C.; Cui, X. H.;
Burgess, K. J. Am. Chem. Soc. 2001, 123, 8878; (b) Perry, M.
C.; Cui, X. H.; Powell, M. T.; Hou, D. R.; Reibenspies, J. H.;
Burgess, K. J. Am. Chem. Soc. 2003, 125, 113.
. Gade, L. H.; Cesar, V.; Bellemin-Laponnaz, S. Angew.
Chem., Int. Ed. 2004, 43, 1014.
Method A: To a solution of rac-E-1,3-diphenyl allyl acetate
(
126 mg, 0.5 mmol) in THF (3 mL) was added
4
(
0.025 mmol) under nitrogen. The mixture was stirred at
room temperature for 15 min. Then a solution of diethyl-
malonate (240 mg, 1.5 mmol) and NaH (35 mg, 1.45 mmol)
in THF (2 mL) was added and the reaction mixture heated
to 50 ꢁC for 15 h.
8. Duan, W. L.; Shi, M.; Rong, G. B. Chem. Commun. 2003,
2916.
9
. (a) Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett.
001, 3, 3225; (b) Van Veldhuizen, J. J.; Garber, S. B.;
Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
24, 4954; (c) Hoveyda, A. H.; Gillingham, D. G.; Van
2
Method B: 3 (0.025 mmol), Pd (dba) (11 mg, 0.0125
2
3
mmol) or Pd(OAc)2 (6 mg, 0.025 mmol), and KOtBu
3 mg, 0.025 mmol) in THF (3 mL) were stirred at room
1
(
Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J.
S.; Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8.
temperature under nitrogen for 30 min, then rac-E-1,3-di-
phenyl allyl acetate (126 mg, 0.5 mmol) was added and stir-
red for 15 min. Then a solution of diethylmalonate
1
0. (a) Thurston, L. S.; Irie, H.; Tani, S.; Han, F.-S.; Liu, Z.-C.;
Cheng, Y.-C.; Lee, K.-H. J. Med. Chem. 1986, 29, 1547; (b)
Reynolds, A. J.; Scott, A. J.; Turner, C. I.; Sherburn, M. S. J.
Am. Chem. Soc. 2003, 125, 12108; (c) Kennedy-Smith, J. J.;
Young, L. A.; Toste, F. D. Org. Lett. 2004, 6, 1325.
(
(
240 mg, 1.5 mmol) and NaH (35 mg, 1.45 mmol) in THF
2 mL) was added and the reaction mixture heated to
5
0 ꢁC for 15 h.

1654
S.-J. Li et al. / Tetrahedron: Asymmetry 17 (2006) 1650–1654
1
1. (a) Viciu, M. S.; Germaneau, R. F.; Navarro-Fernandez, O.;
Stevens, E. D.; Nolan, S. P. Organometallics 2002, 21, 5470;
b) Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett.
002, 4, 4053; (c) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan,
obtained free of charge via www.ccdc.cam.ac.uk/data_
request/cif, or by emailing data_request@ccdc.cam.ac.uk,
or by contacting The Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
(
2
S. P. J. Org. Chem. 2004, 69, 3173; (d) Viciu, M. S.; Navarro,
O.; Germaneau, R. F.; Kelly, R. A., III; Sommer, W.;
Marion, N.; Stevens, E. D.; Cavallo, L.; Nolan, S. P.
Organometallics 2004, 23, 1629.
13. (a) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1,
1307; (b) Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P.
J. Org. Chem. 2001, 66, 7729; (c) Bonnet, L. G.; Douthwaite,
R. E. Organometallics 2003, 22, 4187; (d) Focken, T.;
Rudolph, J.; Bolm, C. Synthesis 2005, 429.
1
2. CCDC 296363 contains the supplementary crystallo-
graphic data for compound 4a. These data can be