Asymmetric cyclization of ω-formyl-1,3-dienes catalyzed by a zerovalent nickel complex in the presence of silanes

Article abstract of DOI:10.1021/jo020438c

A nickel(0)-catalyzed asymmetric cyclization of ω-formyl-1,3-diene in the presence of silanes in which five- or six-membered carbocycles or pyrrolidine derivatives were afforded up to 86% ee by the use of (2R,5R)-2,5-dimethyl-l-phenylphospholane as a monodentate chiral ligand was investigated. The reaction course of this asymmetric cyclization can be explained for by two possible mechanisms: one in which the cyclization proceeds via a π-allylnickel intermediate to produce a cyclized product having an internal olefin in the side chain, and one in which the cyclization proceeds via a σ bond metathesis of silane and the nickel-oxygen bond of oxanickelacycle to produce a cyclized compound having a terminal olefin and/or an internal olefin in the side chain. It was speculated that both of these mechanisms operate in this asymmetric cyclization depending upon the nature of silanes and the reaction conditions.

Full text of DOI:10.1021/jo020438c

Asym m etr ic Cycliza tion of ω-F or m yl-1,3-d ien es Ca ta lyzed by a
Zer ova len t Nick el Com p lex in th e P r esen ce of Sila n es
Yoshihiro Sato, Nozomi Saito, and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, J apan
mori@pharm.hokudai.ac.jp
Received J une 28, 2002
A nickel(0)-catalyzed asymmetric cyclization of ω-formyl-1,3-diene in the presence of silanes in
which five- or six-membered carbocycles or pyrrolidine derivatives were afforded up to 86% ee by
the use of (2R,5R)-2,5-dimethyl-1-phenylphospholane as a monodentate chiral ligand was inves-
tigated. The reaction course of this asymmetric cyclization can be explained for by two possible
mechanisms: one in which the cyclization proceeds via a π-allylnickel intermediate to produce a
cyclized product having an internal olefin in the side chain, and one in which the cyclization proceeds
via a σ bond metathesis of silane and the nickel-oxygen bond of oxanickelacycle to produce a cyclized
compound having a terminal olefin and/or an internal olefin in the side chain. It was speculated
that both of these mechanisms operate in this asymmetric cyclization depending upon the nature
of silanes and the reaction conditions.
SCHEME 1
In tr od u ction
The development of methods for synthesizing cyclic
compounds (i.e., carbocycles or heterocycles) as optically
active forms is very important in modern synthetic
organic chemistry since there are many biologically active
compounds that have complicated cyclic structures.
Transition metal-catalyzed cyclization of prochiral sub-
strates by using chiral ligands is one of the most useful
and promising strategies for the construction of chiral
carbon centers, which are attached to the ring or con-
tained in the ring framework, in cyclic compounds.1,2 On
the other hand, we have recently reported a nickel-
catalyzed cyclization of 1,3-dienes and tethered carbonyl
groups for producing five- to seven-membered ring
carbocycles,3a-c heterocycles,3e and bicyclic heterocycles
(pyrrolizidine and indolizidine)3d,e in a stereoselective
manner (Scheme 1). The utility of this cyclization
prompted us to expand it to an asymmetric cyclization.
We describe herein our results of nickel(0)-catalyzed
asymmetric cyclization of ω-formyl-1,3-diene in the pres-
ence of silanes.4
Resu lts a n d Discu ssion
Con str u ction of F ive-Mem ber ed Ca r bocycles via
Ni(0)-Catalyzed Asym m etr ic Cyclization ofω-For m yl-
1,3-d ien es. To examine the feasibility of expanding this
cyclization to an asymmetric cyclization, we attempted
to cyclize a prochiral substrate 6 using various ligands
in the presence of Et3SiH. The substrate 6 was easily
synthesized from malonate 45 and 5-bromo-1,3-pentadi-
ene6 as shown in Scheme 2. First, treatment of 6 with
Ni(cod)2 (20 mol %) and PPh3 (40 mol %) in the presence
(1) For reviews, see: (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.;
Donovan, R. J . Chem. Rev. 1996, 96, 635 and references therein. (b)
Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49 and
references therein. (c) Trost, B. M. Science 1991, 254, 1471 and
references therein. (d) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995,
34, 259 and references therein. (e) Trost, B. M.; Krische, M. J . Synlett
1998, 1 and references therein. (f) Noyori, R. Asymmetric Catalysis in
Organic Synthesis; Wiley: New York, 1994. (g) Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000.
(2) For recent key examples, see: (a) Goeke, A.; Sawamura, M.;
Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1996, 35, 662. (b)
Hicks, F. A.; Buchwald, S. L. J . Am. Chem. Soc. 1996, 118, 11688. (c)
Shibasaki, M.; Boden, C. D. J .; Kojima, A. Tetrahedron 1997, 53, 7371
and references therein. (d) Fujii, N.; Kakiuchi, F.; Yamada, A.; Chatani,
N.; Murai, S. Chem. Lett. 1997, 425. (e) Murakami, M.; Itami, K.; Ito,
Y. J . Am. Chem. Soc. 1997, 119, 2950. (f) Yamaura, Y.; Hyakutake,
M.; Mori, M. J . Am. Chem. Soc. 1997, 119, 7615. (g) La, D. S.;
Alexander, J . B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock,
R. R. J . Am. Chem. Soc. 1998, 120, 9720. (h) Perch, N. S.; Widenhoefer,
R. A. J . Am. Chem. Soc. 1999, 121, 6960. (i) Hatano, M.; Terada, M.;
Mikami, K. Angew. Chem., Int. Ed. 2001, 40, 249. (j) Mandel, S. K.;
Amin, S. R.; Crowe, W. E. J . Am. Chem. Soc. 2001, 123, 6457. (k)
Seiders, T. J .; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225. (l)
For asymmetric cyclopropanations, see 1f and 1g.
(3) (a) Sato, Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi,
K.; Mori, M. J . Am. Chem. Soc. 1994, 116, 9771. (b) Sato, Y.; Takimoto,
M.; Mori, M. Tetrahedron Lett. 1996, 37, 887. (c) Sato, Y.; Takimoto,
M.; Mori, M. Synlett 1997, 734. (d) Sato, Y.; Saito, N.; Mori, M.
Tetrahedron Lett. 1997, 38, 3931. (e) Sato, Y.; Saito, N.; Mori, M.
Tetrahedron 1998, 54, 1153. (f) Sato, Y.; Takanashi, T.; Hoshiba, M.;
Mori, M. Tetrahedron Lett. 1998, 39, 5579. (g) Sato, Y.; Takanashi, T.;
Mori, M. Organometallics 1999, 18, 4891. (h) Sato, Y.; Takimoto, M.;
Mori, M. J . Am. Chem. Soc. 2000, 122, 1624. (i) Sato, Y.; Takimoto,
M.; Mori, M. Chem. Pharm. Bull. 2000, 48, 1753-1760. (j) Sato, Y.;
Takimoto, M.; Mori, M. J . Synth. Org. Chem. J pn. 2001, 59, 576.
(4) Portions of this work have previously been communicated: Sato,
Y.; Saito, N.; Mori, M. J . Am. Chem. Soc. 2000, 122, 2371.
(5) Curran, D. P.; Shen, W. J . Am. Chem. Soc. 1993, 115, 6051.
(6) Mori, K. Tetrahedron 1974, 30, 3087.
10.1021/jo020438c CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/06/2002
9310
J . Org. Chem. 2002, 67, 9310-9317

Asymmetric Cyclization of ω-Formyl-1,3-dienes
SCHEME 2 a
TABLE 1. Cycliza tion of 6 Usin g Va r iou s Liga n d s
a
Reagents and conditions: (a) 5-bromo-1,3-pentadiene, NaH,
time
(h)
yield
(%)
ee
(%)
SM recovery
(%)
THF, rt; (b) FeCl3.SiO2, acetone.
run
ligand
SCHEME 3
1
2
3
4
5
(S)-BINAP
(R)-H-MOP
(S)-(R)-PPFA
NMDPP
8
62
40
76
27
50
2
2
3
2
13
0
16a
10a
NDb
3a
40
50
43
38
32
a
In these cyclizations, (1R,2R)-7a -I was formed as a major
b
enantiomer. ND: not determined.
F IGURE 1.
of Et3SiH (5 equiv) in degassed THF at room temperature
for 12 h afforded the cyclized product 7a -I in 84% yield
as a sole product (Scheme 3). To determine the stereo-
chemistry of 7a -I, a NOESY experiment was carried out,
and a cross-peak on NOE between H1 and H2 was
observed as shown in Figure 1. On the basis of this result,
the stereochemistry of two substituents at C1 and C2 on
the cyclopentane ring in 7a -I was determined to be a syn
orientation. Next, we tried asymmetric cyclization of 6
with Ni(cod)2 (20 mol %) and various chiral ligands7 (20
mol % (bidentate ligand) or 40 mol % (monodentate
ligand)) in the presence of Et3SiH (5 equiv) in THF (Table
1). Unfortunately, the use of various chiral ligands gave
only a low conversion and an enantiomeric excess of 7a -
I, which was determined by HPLC analysis of 9-I
(DAICEL CHIRALPAK AD, hexane/2-propanol 9/1) after
conversion of 7a -I into 9-I as shown in Scheme 4. In these
asymmetric cyclizations, (1R,2R)-7a -I was produced as
the major enantiomer, and the details for determination
of the absolute configuration of the cyclized product will
be described in the following part.
SCHEME 4
SCHEME 5
SCHEME 6
During the course of our investigation of asymmetric
cyclization using various chiral ligands, we were sur-
prised to find that the reaction of 6 using chiral phos-
phorane 107f (20 mol %) as a ligand smoothly proceeded
at room temperature to afford cyclized products 7a -I and
an isomer 7a -T, having a terminal olefin in the side
chain, in 84% yield as an inseparable mixture (ratio of
4.3:1) (Scheme 5). An inseparable mixture of 7a -I and
7a -T was treated with HF and then subjected to hydro-
genation to give the corresponding cyclopentanol deriva-
tive 11 as a sole product, whose spectral data were
completely identical with those derived from a racemic
7a -I obtained from the previous reaction using PPh3 as
a ligand (Scheme 6). These results revealed that the two
substituents at C1 and C2 positions on the cyclopentane
ring in 7a -T were also controlled to be a syn orientation.
The determination of the enantiomeric excesses of 7a -I
and 7a -T was difficult due to the inseparability of these
products. However, this difficulty could be overcome by
chemoselective Wacker oxidation as follows (Scheme 7):
Treatment of a mixture of 9-I and 9-T, which was derived
from a mixture of 7a -I and 7a -T by the same procedure
as that shown in Scheme 4, with a catalytic amount of
PdCl2 and CuCl under an oxygen atmosphere in dioxane-
H2O gave methyl ketone 12 in 21% yield along with the
recovery of 9-I in 79% yield. This result indicates that
(7) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J . Am. Chem. Soc. 1980, 102, 7932. (b) Uozumi,
Y.; Suzuki, N.; Ogiwara, A.; Hayashi, T. Tetrahedron 1994, 50, 4293.
(c) Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett. 1974,
4405. (d) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993,
32, 566. (e) Morrison, J . D.; Masler, W. F. J . Org. Chem. 1974, 39,
270. (f) Burk, M. J .; Feaster, J . E.; Harlow, R. L. Organometallics 1990,
9, 2653.
J . Org. Chem, Vol. 67, No. 26, 2002 9311

Sato et al.
TABLE 3. Cycliza tion of 6 Usin g Ni(cod )2 a n d 10 in th e
P r esen ce of (EtO)3SiH u n d er Va r iou s Con d ition s
SCHEME 7
temp time
yield (%)
ratioa
ee (%)
run solvent
(°C)
(h) (7c-I + 7c-T)
I/T
(7c-I/7c-T)
TABLE 2. Cycliza tion of 6 Usin g Ni(cod )2 a n d 10 in th e
P r esen ce of Va r iou s Sila n es
1
2
3
4
5
toluene
DMF
CH3CN
DMF
0
0
0
7
3
2
7
8
69
74
79
60
83
5.7/1
12/1
>50/1
>50/1
>50/1
35/24
58/41
61/-
73/-
73/-
-30
CH3CN -30
a
The ratio was determined by 1H NMR.
TABLE 4. Cycliza tion of 6 Usin g Ni(cod )2 a n d 10 in th e
P r esen ce of P h 2MeSiH u n d er Va r iou s Con d ition s
time
(h)
yield (%)
(7-I + 7-T) (7-I/7-T) (7-I/7-T)
ratioa
ee (%)b
run
R3SiH
1c
2c
3d
4d
5d
6d
Et3SiH (a )
5
8
5
2
2
7
84
83
60
80
83
82
4.3/1
>50/1
12/1
1.7/1
1.2/1
1.9/1
2/47
tBuMe2SiH (b)
(EtO)3SiH (c)
Ph3SiH (d )
16/-
46/33
47/53
27/78
21/72
Ph2MeSiH (e)
PhMe2SiH (f)
a
b
The ratio was determined by 1H NMR. The enantiomeric
temp time
yield (%)
ratioa
I/T
ee (%)
(7e-I/7e-T)
excess was determined after conversion of the cyclized products
7b-f into 9-I and 12 in a similar manner to that shown in Scheme
4 and Scheme 7, respectively. c The reaction was carried out in
run solvent
(°C)
(h) (7e-I + 7e-T)
1
2
3
4
toluene
DMF
DMF
0
0
3
3
88
87
73
83
1.7/1
1.1/1
1/1.2
1/1
17/77
39/81
44/86
40/85
d
THF at rt. The reaction was carried out in THF at 0 °C.
-20
CH3CN -20
28
24
only 9-T in the inseparable mixture was converted into
12, while 9-I was intact under the Wacker oxidation
conditions. The compounds 9-I and 12 could be easily
separated by silica gel column chromatography, and the
enantiomeric excesses of 9-I and 12 were determined by
HPLC analysis with a chiral stationary phase column to
be 2% ee (DAICEL CHIRALPAK AD, hexane/2-propanol
9/1) and 47% ee (DAICEL CHIRALPAK AD, hexane/2-
propanol 9/1), respectively.
The ratio was determined by 1H NMR.
a
The same tendency was observed in the cyclization of
6 using Ph2MeSiH as a silane, and the use of a polar
solvent (e.g., DMF, CH3CN) increased the formation of
7e-T and improved the enantiomeric excesses of cyclized
products (Table 4). Namely, in the reaction in DMF at 0
°C, the ratio of 7e-T to 7e-I was 1.1/1 and the enantio-
meric excess of 7e-T increased to 81%. The reaction of 6
in DMF at a lower temperature (-20 °C) gave 7e-T in
slight preference to 7e-I, and the enantiomeric excess of
7e-T reached up to 86%. The use of CH3CN showed the
same tendency, and the reaction of 6 in CH3CN at -20
°C produced 7e-I and 7e-T in 40% ee and 85% ee at a
ratio of 1 to 1, respectively.
The absolute configuration of 7-I was determined by
using the improved Mosher’s method (Scheme 8 and
Figure 2).8 That is, after conversion of 7-I into 9-I via
the above-mentioned Wacker oxidation, hydrolysis of 9-I
(26% ee) with K2CO3 in MeOH followed by treatment
with CH2N2 gave alcohol 13-I. Attempts to convert 13-I
into the corresponding MTPA ester were not successful
due to the steric repulsion between the hydroxyl group
and the neighboring syn-1′-propenyl group. Thus, 13-I
was transformed into anti-alcohol 14-I using the Mit-
sunobu reaction, and this was successfully converted into
Encouraged by the fact that cyclopentanol derivatives
were obtained as optically active forms in the reaction
of 6 using a chiral phosphorane 10 as a ligand, the effects
of silane on the ratio and enantiomeric excess of the
cyclized products were carefully examined, and the
results are summarized in Table 2. The cyclization of 6
using tBuMe2SiH exclusively produced 7b-I in 83% yield,
and the ee increased to 16% (run 2). The use of (EtO)3SiH
improved the enantiomeric excess of 7c-I, having an
internal olefin in the side chain, up to 46% ee, while the
ratio of 7c-I to 7c-T was still relatively high (run 3). It
was interesting that the reaction using Ph2MeSiH af-
forded 7e-T, having a terminal olefin in the side chain,
with good enantioselectivity (78% ee), although the ratio
of 7e-I to 7e-T was low (run 5). On the basis of these
results, we focused on the solvent effects in the reaction
using (EtO)3SiH and Ph2MeSiH. In the reaction using
(EtO)3SiH, it was found that the use of a polar solvent
(e.g., DMF, CH3CN) gave a high ratio and enantioselec-
tivity of 7c-I to 7c-T (Table 3). The reactions of 6 in DMF
(run 4) and CH3CN (run 5) at -30 °C exclusively afforded
7c-I in 73% ee (60% yield) and 73% ee (83% yield),
respectively.
(8) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092. (b) Kusumi, T. J . Synth. Org. Chem. J pn.
1993, 51, 462.
9312 J . Org. Chem., Vol. 67, No. 26, 2002

Asymmetric Cyclization of ω-Formyl-1,3-dienes
SCHEME 8 a
SCHEME 10 a
a
Reagents: (a) K2CO3, MeOH, then CH2N2, Et2O; (b) DEAD,
PPh3, PhCO2H, THF; (c) (S)-MTPA, DCC, DMAP, CH2Cl2.
a
Reagents: (a) NaH, Br(CH2)nOR (n ) 2, R ) TBDPS or n )
3, R ) TBDMS); (b) 5-bromo-1,3-pentadiene, NaH, THF; (c)
DIBAL-H, toluene; (d) Me2C(OMe)2, PPTS; (e) TBAF; (f) PCC,
MS4A; (g) HF, CH3CN; (h) Dess-Martin periodinane, CH2Cl2.
SCHEME 11
F IGURE 2.
SCHEME 9
enantiomer in 9-T was determined to be S at the C1-
position and R at the C2-position. The results indicate
that the absolute configuration of 7-T produced in the
asymmetric cyclization was also S at the C1-position and
R at the C2-position. By using the above-described
methods, the absolute configurations of all cyclized
products in Tables 2 and 3 were determined. It was found
that the cyclized product (1S,2S)-7-I, having an internal
olefin in the side chain, or (1S,2R)-7-T, having a terminal
olefin in the side chain, was produced as the major
enantiomer in all cases.
The cyclization of 19, which was prepared as shown
in Scheme 10, with 10 mol % Ni(cod)2 and ligand 10 in
the presence of (EtO)3SiH in CH3CN at -30 °C also
afforded 22c-I, having a terminal olefin in the side chain,
in 80% yield as a sole product, whose enantiomeric excess
was determined to be 64% ee by conversion of 22c-I to
23-I [HPLC analysis of 23-I (DAICEL CHIRALCEL OJ -
R, CH3CN/H2O 1/1)] (Scheme 11).
Con str u ction of Six-Mem ber ed Ca r bocycles a n d
Nitr ogen -Con ta in in g F ive-Mem ber ed Heter ocycles
via Ni(0)-Ca t a lyzed Asym m et r ic Cycliza t ion of
ω-F or m yl-1,3-d ien es. Next, asymmetric cyclizations of
various substrates were investigated. The cyclization of
21, which was prepared as shown in Scheme 10, using
(EtO)3SiH in DMF at -30 °C was carried out. An
inseparable mixture of six-membered ring compounds
24c-I and 24c-T was obtained in a total yield of 51% at
a ratio of 1 to 2.6 (Table 5, run 1). The cyclization of 21
using Ph2MeSiH in DMF afforded 24e-I in preference to
24e-T at a ratio of 7.3 to 1 in a total yield of 61% (run 2).
the corresponding (S)-MTPA ester 15-I. The (S)-MTPA
ester 15-I was obtained as a mixture of two diastereomers
(26% de), and the chemical shifts of each diastereomer
were carefully assigned on the basis of 2D NMR. The
1
values of ∆δ ) |δmajor| - |δminor| in the H NMR spectrum
of (S)-MTPA ester 15-I were calculated and are shown
in Figure 2. All assigned protons with positive and
negative ∆δ values are actually found on the right and
left sides of the MTPA plane, respectively. On the basis
of these results, the absolute configuration of the major
diastereomer in 15-I was determined to be R at the C1-
position and S at the C2-position. These results indicate
that the absolute configuration of the product 7-I in the
cyclization of 6 using chiral phosphorane 10 was 1S and
2S. On the other hand, the absolute configuration of 7-T
was determined by a combination of the chemical cor-
relation and HPLC analysis with a chiral stationary
phase column. It was found that 9-I could be converted
into the above-mentioned methyl ketone 12 via Wacker
oxidation by changing the solvent from dioxane to DMF,
and (1S,2S)-12 was synthesized from (1S,2S)-9-I in 83%
yield (Scheme 9). By comparison of the HPLC chart of
the authentic (1S,2S)-12 with that of 12 derived from a
mixture of 9-I and 9-T by Wacker oxidation in dioxane
(Scheme 7), the absolute configuration of the major
J . Org. Chem, Vol. 67, No. 26, 2002 9313

Sato et al.
TABLE 5. Cycliza tion of 21 Usin g Ni(cod )2 a n d 10
time
yield (%)
ratiob
ee (%)
runa
R3SiH
(EtO)3SiH (c) 24
Ph2MeSiH (e)
(h) (24-I + 24-T) 24-I/24-T (24-I/24-T)
1
2
51
61
1/2.6
7.3/1
42/66
61/66
9
a
The reaction was carried out at -30% °C (run 1) or 0 °C (run
2). The ratio was determined by 1H NMR.
b
F IGURE 3.
SCHEME 12
SCHEME 14
TABLE 6. Cycliza tion of 28 Usin g Ni(cod )2 a n d 10
SCHEME 13
time
yield (%)
ratiob
ee (%)
runa
R3SiH
(h) (29-I + 29-T) 29-I/29-T (29-I/29-T)
1
2
(EtO)3SiH (c)
Ph2MeSiH (e) 42
6
60
22
4.6/1
1/2.4
48/41
10/67
The enantiomeric excesses of the cyclized products shown
in Table 5 were determined using the above-mentioned
chemoselective Wacker oxidation. That is, after conver-
sion of an inseparable mixture of 24-I and 24-T (24-I/
24-T 1/2.6, run 1, Table 5) into the corresponding
benzoates 25-I and 25-T, the mixture of 25-I and 25-T
was subjected to the Wacker oxidation in a manner
similar to that in the case of the five-membered ring
system (Scheme 12), and 25-I and 26 were obtained in
25% yield and 73% yield, respectively. The compounds
25-I and 26 could be easily separated by silica gel col-
umn chromatography, and their enantiomeric excesses
were determined by HPLC analysis [25-I: DAICEL
CHRALCEL OJ -R, CH3CN/H2O 99/1; 26: DAICEL
CHIRALCEL OJ , hexane/2-propanol 9/1]. Based on a
comparison of HPLC charts, it was also found that the
same enantiomers of 24-I and 24-T were produced as the
major enantiomers in both reactions of runs 1 and 2 in
Table 5.
The absolute configuration of 25-I was determined to
be R at the C1-position and S at the C2-position by the
improved Mosher’s method after conversion of 25-I into
27-I in a manner similar to that described above (Scheme
13 and Figure 3). This result indicates that (1R,2S)-24-I
was produced as the major enantiomer in the asymmetric
cyclization of 21. On the other hand, the absolute
configuration of 26 was determined as follows (Scheme
14): (1R,2S)-25-I was converted into (1R,2S)-26 via
Wacker oxidation in DMF, and then by the comparison
of HPLC chart of authentic (1R,2S)-26 with that of 26
derived from a mixture of 25-I and 25-T as shown in
a
The reaction was carried out in CH3CN (run 1) or DMF (run
2) at 0 °C. The ratio was determined by 1H NMR.
b
Scheme 12, the absolute configuration of the major
enantiomer in 25-T was determined to be R at the C1-
position and S at the C2-position. This result indicates
that the absolute configuration of 24-T obtained in the
asymmetric cyclization of 21 was also R at the C1-
position and S at the C2-position.
It is noteworthy that this asymmetric cyclization is
applicable to the construction of a pyrrolidine ring (Table
6). The cyclization of 283e with 10 mol % Ni(cod)2 and
ligand 10 in the presence of (EtO)3SiH in CH3CN gave
29c-I (48% ee) and 29c-T (41% ee) (ratio of 4.6 to 1) in a
total yield of 60% (run 1).9 On the other hand, the
cyclization of 28 using Ph2MeSiH produced 29e-T (67%
ee) in preference to 29e-I (10% ee) in a ratio of 2.4 to 1
(run 2). In both cyclizations, (1R,2R)-29-I and (1R,2R)-
29-T were produced as the major enantiomers.9 It was
found that the pyrrolidine system showed the same
tendency as that of the five-membered carbocyclic system,
in which the use of (EtO)3SiH increased the formation of
29-I having an internal olefin in the side chain, while
the reaction using Ph2MeSiH reversed the ratio of 29-I
to 29-T.
(9) The enantiomeric excesses and the absolute configurations of
29-I and 29-T were determined by procedures similar to those used
for the above-mentioned five- and six-membered carbocyclic systems.
See Supporting Information.
9314 J . Org. Chem., Vol. 67, No. 26, 2002

Asymmetric Cyclization of ω-Formyl-1,3-dienes
SCHEME 15
Mech a n ism of Ni(0)-Ca ta lyzed Asym m etr ic Cy-
cliza tion of ω-F or m yl-1,3-d ien es. A possible mecha-
nism of the asymmetric cyclization of ω-formyl-1,3-diene
in the presence of silanes is shown in Scheme 15. The
formation of 37-I having an internal olefin in the side
chain can be explained by the mechanism via a π-al-
lylnickel intermediate (Scheme 15, Path A).3h That is,
nickel hydride complex 33 would be initially formed by
oxidative addition of silane (R3SiH) to a zerovalent nickel
complex, and this complex would react with the 1,3-diene
moiety of 34 to give π-allylnickel intermediate 35. The
reaction of the aldehyde in a tether of 35 with the
π-allylnickel moiety would give 36, and the cyclized
product 37-I having an internal olefin in the side chain
would be produced through reductive elimination from
36. On the other hand, the formation of 37-T having a
terminal olefin in the side chain cannot be explained by
this mechanism, and it was speculated that 37-T is
produced via path B, which involves a σ bond metathesis
of silanes and the nickel-oxygen bond of oxanickela-
cycle.10 Namely, oxidative cycloaddition of both olefin and
aldehyde moieties of 34 to a zerovalent nickel complex
would occur to give oxanickelacycle 38. σ bond metathesis
of R3SiH and the nickel-oxygen bond of 38 via 39 would
produce nickel hydride intermediate 40, which would
afford 37-T, having a terminal olefin in the side chain,
directly by reductive elimination. The formation of 37-I,
having an internal olefin in the side chain, also might
be explainable by path B through reductive elimination
from 40 via a π-allylnickel intermediate. As described
above, both the ratio and enantiomeric excess of the
cyclized products, having an internal olefin or a terminal
olefin in the side chain, varied depending upon the
substrates and/or silanes. Thus, we speculate that both
mechanisms of path A and path B operate in this
asymmetric cyclization.
ligand. The reaction course of this asymmetric cyclization
can be explained for by two possible mechanisms: one
in which the cyclization proceeds via a π-allylnickel
intermediate to produce a cyclized product having an
internal olefin in the side chain, and one in which the
cyclization proceeds via a σ bond metathesis of silane and
the nickel-oxygen bond of oxanickelacycle to produce a
cyclized compound having a terminal olefin and/or an
internal olefin in the side chain. The present results
should pave the way to the establishment of a novel
strategy for construction of cyclic compounds as optically
active forms.
Exp er im en ta l Section
Gen er a l. All manipulations were performed under an argon
atmosphere unless otherwise mentioned. All solvents and
reagents were purified when necessary using standard pro-
cedures. Column chromatography was performed on silica gel
60 (Merck, 70-230 mesh), and flash chromatography was
performed on silica gel 60 (Merck, 230-400 mesh).
Gen er a l P r oced u r e for Ni(0)-Ca ta lyzed Cycliza tion in
th e P r esen ce of Sila n e. To a solution of Ni(cod)2 (10 or 20
mol % to the substrate) and ligand (20 or 40 mol % to the
substrate) in degassed solvent (ca. 0.01 M) was added a silane
(5 equiv of substrate) at 0 °C, and the mixture was stirred at
the same temperature. To the solution was added a solution
of substrate in degassed solvent (ca. 0.08 M) at the tempera-
ture indicated in the text, and the mixture was stirred at the
same temperature. After removal of the solvent, the crude
product was purified by silica gel column chromatography to
give the cyclized product.
Typ ica l P r oced u r e for Asym m etr ic Cycliza tion of 6
Usin g Ch ir a l P h osp h or a n e 10 in th e P r esen ce of Et3SiH
(Sch em e 5 a n d Ta ble 2, r u n 1). According to the General
Procedure for Cyclization, the crude product, which was
prepared from Ni(cod)2 (7.7 mg, 0.03 mmol), 10 (10.8 mg, 0.056
mmol), 6 (67 mg, 0.28 mmol), and Et3SiH (0.23 mL, 1.4 mmol)
in THF (5.6 mL) at room temperature for 5 h, was purified by
column chromatography on silica gel (hexane/Et2O 10/1) to give
an inseparable mixture of 7a -I and 7a -T (84 mg, total yield
84%, ratio of 4.3:1).
Con clu sion s
A nickel(0)-catalyzed asymmetric cyclization of ω-formyl-
1,3-dienes in the presence of silanes was investigated,
and it was found that five- or six-membered carbocycles
or pyrrolidine derivatives were afforded in ee up to 86%
by the use of phosphorane 10 as a chiral monodentate
Typ ica l P r oced u r e for Sep a r a tion of a n In sep a r a ble
Mixtu r e of 7-I a n d 7-T in to 9-I a n d 12 via Ch em oselective
Wa ck er Oxid a tion (Sch em e 7). To a mixture of 7a -I and
7a -T (84 mg, 0.23 mmol, ratio of 4.3:1) in CH3CN (1.0 mL)
was added 1.0 mL of HF-CH3CN solution (prepared by mixing
a concentrated HF aq solution with CH3CN (ratio of 1:9)) and
the mixture was stirred at room temperature for 20 min. To
the mixture was added a saturated NaHCO3 aq solution, and
the aqueous layer was extracted with Et2O. The organic layer
was washed with brine and dried over Na2SO4. After re-
moval of the solvent, the mixture of the alcohols was treated
(10) Recently, σ bond metathesis of silanes and the nickel/oxygen
bond of oxanickelacycle has also been proposed by Montgomery in a
Ni(0)-catalyzed cyclization of ynals in the presence of silanes. See:
Tang, X.-Q.; Montgomery, J . J . Am. Chem. Soc. 1999, 121, 6098 and
references cited therein.
J . Org. Chem, Vol. 67, No. 26, 2002 9315

Sato et al.
with BzCl (0.26 mL, 2.2 mmol) and a catalytic amount of
DMAP in pyridine (1.5 mL) at 50 °C for 18 h. After the usual
workup, the residue was purified by column chromatography
on silica gel (hexane/Et2O 3/1) to give an inseparable mix-
ture of 9-I and 9-T (77 mg, total yield 95%, ratio of 4.3:1).
To a mixture of benzoate 9-I and 9-T (37 mg, 0.11 mmol,
ratio of 4.3:1) in 1,4-dioxane-H2O (10:1, 1.5 mL) were added
PdCl2 (1.9 mg, 0.01 mmol) and CuCl (1.4 mg, 0.01 mmol), and
the mixture was stirred at room temperature for 1.5 h under
an atmosphere of oxygen. The mixture was diluted with Et2O,
and 10% HCl aq solution was added to the mixture. The
aqueous layer was extracted with Et2O, and the organic layer
was washed with brine and dried over Na2SO4. After re-
moval of the solvent, the residue was purified by column
chromatography on silica gel (hexane/EtOAc 5/1 to 2/1) to give
12 (8 mg, 21%), and unchanged 9-I (29 mg, 79%) was
recovered.
Sp ectr a l d a ta for 9-I: IR (neat) 1736, 1720, 1654, 1602,
1114 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.53 (dd, J ) 6.3, 1.3
Hz, 3 H), 2.37 (dd, J ) 13.6, 7.8 Hz, 1 H), 2.53 (dd, J ) 13.6,
11.8 Hz, 1 H), 2.57 (dd, J ) 15.2, 1.7 Hz, 1 H), 2.63 (dd, J )
15.2, 4.4 Hz, 1 H), 2.77 (m, 1 H), 3.56 (s, 3 H), 3.68 (s, 3 H),
5.34 (m, 1 H), 5.37 (ddq, J ) 15.3, 7.3, 1.3 Hz, 1 H), 5.50 (dq,
J ) 15.3, 6.3 Hz, 1 H), 7.30-7.41 (m, 2 H), 7.48 (m, 1 H), 7.88-
7.93 (m, 2 H); EI-LRMS m/z 346 (M+), 315, 278, 241, 224, 164,
105, 77, 59; EI-HRMS calcd for C19H22O6 346.1417, found
346.1402; [R]23D +26.8 (c 1.66, CHCl3, 73% ee) (for (1S,2S)-9-I
derived from 7c-I in Table 3, run 4)
After removal of the solvent, the residue was purified by
column chromatography on silica gel (hexane/Et2O 5/1) to give
the benzoate as a colorless oil (71 mg, 58%). IR (neat) 1736,
1722, 1654, 1602, 1270 cm-1; 1H NMR (270 MHz, CDCl3) δ
1.65 (d, J ) 6.3 Hz, 3 H), 2.02 (dd, J ) 13.5, 9.0 Hz, 1 H), 2.44
(dd, J ) 14.5, 5.1 Hz, 1 H), 2.76 (dd, J ) 13.5, 7.9 Hz, 1 H),
2.86 (dd, J ) 14.5, 6.8 Hz, 1 H), 2.88 (m, 1 H), 3.01 (s, 3 H),
3.75 (s, 3 H), 5.12 (m, 1 H), 5.43 (dd, J ) 15.4, 7.3 Hz, 1 H),
5.58 (dq, J ) 15.4, 6.3 Hz, 1 H), 7.43 (dd, J ) 7.7, 7.7 Hz, 2
H), 7.55 (dd, J ) 7.7, 7.7 Hz, 1 H), 8.00 (d, J ) 7.7 Hz, 2 H);
EI-LRMS m/z 346 (M+), 315, 224, 164, 105, 77; EI-HRMS calcd
for C19H22O6 346.1416, found 346.1438; [R]23 -8.60 (c 2.42,
D
CHCl3, 26% ee).
(1R,2S)-4,4-Bism eth oxyca r bon yl-2-[(1E)-p r op en yl]cy-
clop en ta n -1-ol (14-I). According to the procedure described
above, 14-I was prepared in 98% yield (48 mg) by the reaction
of the above benzoate (71 mg, 0.21 mmol) and K2CO3 (142 mg,
1.0 mmol) in CH3OH (3 mL) at room temperature for 36 h
followed by treatment of CH2N2. IR (neat) 3432, 1734, 1640,
1
1168, 1076 cm-1; H NMR (270 MHz, CDCl3) δ 1.68 (dd, J )
6.5, 1.2 Hz, 3 H), 1.05 (dd, J ) 13.6, 10.1 Hz, 1 H), 2.01 (br d,
J ) 4.4 Hz, 1 H), 2.16 (dd, J ) 14.0, 7.2 Hz, 1 H), 2.43 (m, 1
H), 2.57 (dd, J ) 13.6, 7.7 Hz, 1 H), 2.63 (dd, J ) 14.0, 7.2 Hz,
1 H), 3.73 (s, 3 H), 3.75 (s, 3 H), 3.89 (m, 1 H), 5.31 (ddq, J )
15.2, 7.8, 1.2 Hz, 1 H), 5.58 (ddq, J ) 15.2, 1.0, 6.5 Hz, 1 H);
EI-LRMS m/z 224 (M+ - H2O), 164, 105, 59; EI-HRMS calcd
for C12H16O4 224.1048 (M+ - H2O), found 224.1051; [R]24
-3.23 (c 1.93, CHCl3, 26% ee).
D
Sp ectr a l d a ta for 12: IR (neat) 1734, 1720, 1718, 1654,
1602, 1114 cm-1 1H NMR (400 MHz, CDCl3) δ 2.10 (s, 3
;
Con ver sion of 14-I in to (S)-MTP A Ester 15-I. To a
solution of 14-I (28 mg, 0.11 mmol, 26% ee) in CH2Cl2 (1.5
mL) were added DCC (36 mg, 0.17 mmol), (S)-(-)-R-methoxy-
R-(trifluoromethyl)phenylacetic acid (40 mg, 0.17 mmol), and
DMAP (22 mg, 0.18 mmol), and the mixture was stirred at
room temperature for 15.5 h. The mixture was diluted with
Et2O, 10% HCl aq solution was added to the mixture, and
the solution was stirred at room temperature for 1 h. The
aqueous layer was extracted with Et2O, and the organic layer
was washed with a saturated NaHCO3 aq solution and brine
and dried over Na2SO4. After removal of the solvent, the
residue was purified by column chromatography on silica gel
(hexane/Et2O 5/1 to 3/1) to give two diastereomers as an
inseparable mixture (46 mg, 87%, 26% de). The NMR spec-
tral data (including COSY spectrum) of the mixture were
fully considered by application of the improved Mosher’s
method, and it indicates that (1R,2S)-15-I was a major
diastereomer. (1R,2S)-15-I: 1H NMR (500 MHz, CDCl3) δ 1.61
(d, J ) 6.4 Hz, 3 H), 1.97 (dd, J ) 13.6, 10.5 Hz, 1 H), 2.38
(dd, J ) 14.4, 6.5 Hz, 1 H), 2.58 (dd, J ) 13.6, 7.8 Hz, 1 H),
2.68 (m, 1 H), 2.83 (dd, J ) 14.4, 7.4 Hz, 1 H), 3.53 (s, 3 H),
3.69 (s, 3 H), 3.74 (s, 3 H), 5.14 (ddd, J ) 7.4, 7.4, 6.5 Hz, 1
H), 5.30 (dd, J ) 15.3, 8.1 Hz, 1 H), 5.43 (dq, J ) 15.3, 6.4 Hz,
1 H), 7.36-7.43 (m, 3 H), 7.49-7.51 (m, 2 H). (1S,2R)-15-I:
1H NMR (500 MHz, CDCl3) δ 1.66 (d, J ) 6.3 Hz, 3 H), 1.95
(dd, J ) 13.6, 11.7 Hz, 1 H), 2.23 (dd, J ) 14.5, 6.4 Hz, 1 H),
2.63 (dd, J ) 13.6, 7.9 Hz, 1 H), 2.77 (m, 1 H), 2.85 (dd, J )
14.5, 7.3 Hz, 1 H), 3.53 (s, 3 H), 3.69 (s, 3 H), 3.74 (s, 3 H),
5.12 (ddd, J ) 7.3, 7.3, 6.4 Hz, 1 H), 5.30 (dd, J ) 15.1, 7.9
Hz, 1 H), 5.56 (dq, J ) 15.1, 6.3 Hz, 1 H), 7.36-7.43 (m, 3 H),
7.49-7.51 (m, 2 H).
H), 2.39 (dd, J ) 13.6, 11.1 Hz, 1 H), 2.49-2.52 (m, 2 H), 2.63
(dd, J ) 15.2, 1.2 Hz, 1 H), 2.67-2.78 (m, 3 H), 3.62 (s, 3 H),
3.75 (s, 3 H), 5.51 (m, 1 H), 7.42-7.49 (m, 2 H), 7.57 (m, 1 H),
7.94-7.99 (m, 2 H); EI-LRMS m/z 363 (M+ + H), 362 (M+),
331, 319, 305, 240, 198, 183, 105, 77; EI-HRMS calcd for
C
19H23O7 (M+ + H) 363.1444, found 363.1416; [R]24 -3.7 (c
D
1.36, CHCl3, 86% ee) (for (1S,2S)-12 derived from 7e-T in Table
4, run 3)
The enantiomeric excess of 9-I or 12 was determined by
HPLC analysis [DAICEL CHIRALPAK AD (hexane/2-propanol
9/1) or DAICEL CHIRALPAK AD (hexane/2-propanol 9/1),
respectively]. The enantiomeric excesses of other cyclized
products in Tables 2-4 were determined by HPLC analysis
after transformation to 9-I and 12 by similar procedures as
those for 7a -I and 7a -T.
Typ ica l P r oced u r e for Deter m in a tion of Absolu te
Con figu r a tion s of th e Cyclized P r od u cts 7-I a n d 7-T
(Sch em es 8 a n d 9). (1S,2S)-4,4-Bism eth oxyca r bon yl-2-
[(1E)-p r op en yl]cyclop en ta n -1-ol (13-I). To a solution of 9-I
(341 mg, 0.98 mmol, 26% ee) in CH3OH (10 mL) was added
K2CO3 (677 mg, 4.9 mmol), and the mixture was stirred at
room temperature for 20 h. After the usual workup, the crude
material was treated with an excess amount of CH2N2 in Et2O,
and the mixture was concentrated in vacuo. The residue was
purified by column chromatography on silica gel (hexane/
EtOAc 4/1) to give 13-I as a colorless oil (225 mg, 95%). IR
(neat) 3526, 1732, 1654, 1198, 1142 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.71 (dd, J ) 6.2, 1.3 Hz, 3 H), 1.82 (br d, J ) 3.4
Hz, 1 H), 2.31-2.45 (m, 3 H), 2.49 (dd, J ) 14.7, 1.7 Hz, 1 H),
2.61 (m, 1 H), 3.72 (s, 3 H), 3.75 (s, 3 H), 4.15 (m, 1 H), 5.50
(dq, J ) 15.5, 1.3 Hz, 1 H), 5.61 (dq, J ) 15.5, 6.2 Hz, 1 H);
EI-LRMS m/z 242 (M+), 224, 174, 164, 145, 113, 105, 68, 59;
EI-HRMS calcd for C12H18O5 242.1154, found 242.1176; [R]22
+7.27 (c 1.15, CHCl3, 26% ee).
D
Other spectral data of a mixture of (1R,2S)-15-I and (1S,2R)-
15-I: IR (neat) 1738, 1736, 1654, 1252 cm-1; EI-LRMS m/z
427 (M+ - OMe), 224, 189, 165, 105, 77, 59; EI-HRMS calcd
for C21H22F3O6 (M+ - OMe) 427.1368, found 427.1379.
(1R,2S)-1-Ben zoyloxy-4,4-bism eth oxyca r bon yl-2-[(1E)-
p r op en yl]cyclop en ta n e. To a solution of 13-I (85 mg, 0.35
mmol, 26% ee) in THF (2 mL) were added PPh3 (185 mg, 0.70
mmol), benzoic acid (102 mg, 0.46 mmol), and DEAD (136 mg,
0.78 mmol), and the mixture was stirred at room temperature
for 4 h. To the mixture was added a saturated NaHCO3 aq
solution, and the aqueous layer was extracted with Et2O. The
organic layer was washed with brine and dried over Na2SO4.
Con ver sion of (1S,2S)-9-I in to (1S,2S)-12. According to
a procedure similar to that described above, the crude product,
which was prepared from (1S,2S)-9-I (40 mg, 0.12 mmol, 46%
ee), PdCl2 (2.0 mg, 0.011 mmol), and CuCl (1.4 mg, 0.014
mmol) in DMF-H2O (10:1, 1.5 mL) at room temperature for
9316 J . Org. Chem., Vol. 67, No. 26, 2002

Asymmetric Cyclization of ω-Formyl-1,3-dienes
45 h under an atmosphere of oxygen, was purified by column
chromatography on silica gel (hexane/EtOAc 10/1) to give
(1S,2S)-12 as a colorless oil (35 mg, 83%, 46% ee), whose
spectral data were identical with those described above.
lowships of the J apan Society for the Promotion of
Sciences for Young Scientists for support.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
synthesis of the substrates and its spectral data; proce-
dures for determination of the enantiomeric excess and the
absolute configuration of cyclized products 22c-I, 24, and
29, and spectral data for the related compounds; 1H NMR
spectra for new compounds lacking elemental analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This work was supported in part
by the Research Foundation for Pharmaceutical Sci-
ences and the Uehara Memorial Foundation, and by a
Grant-in-aid from the Ministry of Education, Culture,
Sports, Science, and Technology of J apan, which are
gratefully acknowledged. N.S. thanks Research Fel-
J O020438C
J . Org. Chem, Vol. 67, No. 26, 2002 9317