A tandem reaction of organozinc reagent prepared from palladium-catalyzed umpolung method: Diastereoselective formation of cyclohexene derivatives bearing three adjacent stereocenters

Article abstract of DOI:10.1039/c0ob00806k

In the presence of a palladium catalyst, treatment of γ-acyloxy- α,β-unsaturated ketone with bis(iodozincio)methane caused umpolung of π-allylpalladium to give a zinc dienolate. Thus formed zinc species afforded a cyclohexene derivative via a self-condesation reaction. It is noteworthy that the three adjacent stereogenic centers were created in a single process with quite high diastereoselectivity. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c0ob00806k

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PAPER
A tandem reaction of organozinc reagent prepared from palladium-catalyzed
umpolung method: diastereoselective formation of cyclohexene derivatives
bearing three adjacent stereocenters†
Mutsumi Sada, Kenichi Nomura and Seijiro Matsubara*
Received 1st October 2010, Accepted 5th November 2010
DOI: 10.1039/c0ob00806k
In the presence of a palladium catalyst, treatment of g-acyloxy-a,b-unsaturated ketone with
bis(iodozincio)methane caused umpolung of p-allylpalladium to give a zinc dienolate. Thus formed
zinc species afforded a cyclohexene derivative via a self-condesation reaction. It is noteworthy that the
three adjacent stereogenic centers were created in a single process with quite high diastereoselectivity.
a,b-unsaturated ketone 2, an allylic zinc reagent bearing a ketone
group would be prepared and it would perform another type of
tandem reaction. In fact, in the presence of a palladium catalyst,
the reaction product dramatically changed, and a cyclohexene
derivative 4 was obtained via a self-condensation reaction7 with
high diastereoselectivity (Scheme 2). This reaction would be an
efficient method to create adjacent multiple stereocenters in a
single operation.8 While umpolung of a simple allylic acetate with
palladium catalyst and diethylzinc was developed and shown to
be useful for C–C bond–forming reactions by Tamaru, umpolung
of g-acylallylic acetate has not been shown.
Introduction
A tandem reaction is one of the most efficient reactions in
organic syntheses.1 It enables one to construct plural bonds and
stereocenters in a single process, and therefore it is often applied to
the formation of structurally complex compounds. However, there
still has been a significant challenge to succeed in a stereoselective
construction of multiple stereocenters, in particular, adjacent
stereocenters containing a highly substituted carbon atom such as
a tertiary alcohol, which are often found as key units in complex
natural products.2
In the course of our study on bis(iodozincio)methane (1),3 we
recently reported a novel tandem reaction using the gem-dizinc 1
as a nucleophile to g-acyloxy-a,b-unsaturated ketone 24 to afford
a 1,3-diketone 3 efficiently via three sequential steps (Scheme 1).5
In this reaction, the acyloxy group in the substrate was used as an
electrophilic moiety for the intramolecular tandem reaction.
Scheme 2 Umpolung of g-acyloxyenone 2 with dizinc 1.
Scheme 1 Tandem reactions of g-acyloxyenone 2 with dizinc 1.
As another possibility of bis(iodozincio)methane (1), the dizinc
1 could be an efficient reagent for umpolung of p-allylpalladium
species.6 When this umpolung method is applied to g-acyloxy-
The active species 6, an allylic zinc reagent bearing a ketone
group, would be in equilibrium with a zinc dienolate 6¢.9 Although
an enone has been frequently used as Michael accepter, its
alternative use as dienol has not attracted much attention except
for the vinylogous aldol reaction.10 Especially, it has been a
challenging subject to perform a reaction of the dienolate with
unsaturated ketones, since there are many possible adducts and in
most reported cases cyclized products were obtained only as by-
products.11 Encouraged by this fact, we decided to examine this
reaction in detail.
Department of Material Chemistry, Graduate School of Engineering, Kyoto
University, Kyoutodaigaku-katsura, Nishikyo, Kyoto, 615-8510, Japan.
E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp; Fax: +81 75 383
2438; Tel: +81 75 383 7130
† Electronic supplementary information (ESI) available. CCDC reference
number 773947. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob00806k
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Table 1 Screening of organozinc reagents in the palladium-catalyzed
the formation of 3a, but the yield of 4a was still unsatisfying
(entries 3, 8). Increasing the catalyst loading to 3 mol% gave the
improved yield of 4a (entries 4–7), and we set the condition of
entry 7 as the optimal. It is notable that the only two diastereomers
were generated in this reaction even though the cyclic product 4a
contained three stereogenic centers, and its diastereoselectivity was
quite high (4a:4¢a = 14 : 1, entry 7).
cyclization reactiona
Entry
Organozinc
Productb
Recoveryb
The structure of ((1R*,5R*,6S*)-6-benzoyl-5-hydroxy-5-
phenylcyclohex-3-enyl)methyl acetate (4a) was determined by
X-ray crystallographic analysis (Fig. 1). The structure of the
obtained diastereomer, ((1R*,5S*,6S*)-6-benzoyl-5-hydroxy-5-
1
2
3
4
5
6
7
CH2(ZnI)2
MeZnI
Me2Zn
4a
67%
—
8.9%
34%
—
82%
89%
—
—
—
4a
4a
Et2Zn
1
Me3ZnLi
tBu3ZnLi
tBu4ZnLi2
Complex mixture
Complex mixture
Complex mixture
phenylcyclohex-3-enyl)methyl acetate (4¢a), was estimated by H
NMR analysis. Both coupling constants between the protons on
C5 and C6 in 4a and 4¢a were 12 Hz, those are typical for diaxial
protons.
—
a To a solution of 2a (1.0 equiv) and Pd(PPh3)4 (1 mol%) in THF (2 mL),
organozinc reagent (1.2 equiv) was added dropwise at 25 ◦C, and whole
was stirred for 12 h. b The yields were determined by 1H NMR using
bromoform as an internal standard.
Table 2 Optimization of the reaction conditionsa
Entry x (mol%) y (equiv.) z (mL) T/◦C 4a (%)b 4¢a (%)b 3a (%)b
1
2
3
4
5
6
7
8
1
1
1
10
5
3
3
3
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.0
2
10
2
2
5
5
5
5
25
25
0
25
25
25
25
0
67
68
60
52
72
77
77
61
4.4
4.0
2.7
2.2
3.7
4.8
5.5
4.4
11
21
Fig. 1 ORTEP of 4a (Triclinic, a = 6.0102(6), b = 10.0194(9), c =
◦
3
˚
˚
15.9053(15) A, b = 83.245(2) , V = 914.94(15) A , Z = 2, rc = 1.272 Mg
6.6
—
1.8
7.7
5.5
1.6
m-3, l(Moka) = 0.71073 A, T = 296 K, qmax = 27.0◦,, R = 0.0150 for 3892
˚
reflections (I > 2d (I)).
Under the optimal conditions, we treated various g-acyloxy-
a,b-unsaturated ketones 2 with the dizinc 1, and the results are
listed in Table 3. This reaction proceeded efficiently in every case,
and afforded the corresponding cyclohexene derivative 4 with
high diastereoselectivity. The excellent selectivity was observed
especially in the case that R1 was 2-naphthyl or p-bromophenyl
group (entries 2, 5). Not only acetate but also benzoate or
a To a solution of 2a (1.0 equiv.) and Pd(PPh3)4 in THF, 1 was added
dropwise, and whole was stirred for 1–12 h. b The yields were determined
by 1H NMR using bromoform as an internal standard.
Results and discussion
Treatment of g-acylallylic acetate with various organozinc ragents
in the presence of palladium catalyst was examined as shown in
Table 1. A reaction of (E)-4-acetoxy-1-phenyl-2-buten-1-one (2a,
0.5 mmol) with 1 (0.6 mmol, 0.5 M in THF) in the presence
of Pd(PPh3)4 (1 mol%) in THF at 25 ◦C for 12 h gave a cyclic
product 4a in 67% yield (entry 1, Table 1). Methylzinc iodide and
dimethylzinc did not afford the product 4a efficiently; most of
the starting material was recovered (entries 2, 3). In comparison,
diethylzinc gave 4a, but in a lower yield than in the case of using
1, with a lot of by-products (entry 4). Using ate complexes, the
reactions resulted in complex mixtures, probably because of the
higher nucleophilicity (Entries 5–7).12 From these results, the gem-
dizinc 1 was shown to be a specific reagent for this reaction.
To optimize the reaction conditions, we examined the reaction
using dizinc 1 with various conditions. The results are listed in
Table 2. A smaller amount of palladium catalyst lead to a more
formation of 1,3-diketone 3a (entry 1), because by-product 3a was
formed via a tandem reaction initiated by a direct nucleophilic
attack of 1 to 2a without Pd catalyst as shown in Scheme 1.
Lowering the reaction temperature to 0 ◦C evidently prevented
Table 3 Diastereoselective formation of a cyclohexene derivative 4 via the
tandem reactiona
Entry
R1
R2
4 + 4¢ (%)b
dr
1
2
3
4
5
6
7
8
Ph
Me
Me
Me
Me
Me
Me
iPr
2a
2b
2c
2d
2e
2f
83
74
72
67
82
72
78
81
4a
4b
4c
4d
4e
4f
14/1
33/1
9.0/1
3.5/1
33/1
2.1/1
16/1
14/1
2-Naphthyl
p-Tolyl
p-MeOC6H4
p-BrC6H4
PhCH2CH2
Ph
2g
2h
4g
4h
Ph
Ph
a To a solution of 2 (1.0 equiv) and Pd(PPh3)4 (3 mol%) in THF (5
mL), bis(iodozincio)methane (1, 1.0 equiv) was added dropwise at 25 ◦C,
and whole was stirred for 1.5–6 h. b The yields were determined by 1H
NMR analyses. All of the products were isolated by silica gel column
chromatography for the identification.
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isopropanoate was applicable to this reaction to afford the product
4 with high selectivity (entries 7, 8). As this reaction should proceed
under a relatively mild condition, it could tolerate many functional
groups such as esters and tertiary alcohols in the products.
The plausible reaction pathway was shown in Scheme 2.
Oxidative addition of g-acyloxy-a,b-unsaturated ketone 2 to pal-
ladium(0) forms the p-allylpalladium species 5. Transmetalation
between 5 and bis(iodozincio)methane (1)6b gives the active zinc
species 6 or 6¢, which attacks the enone 2 in a 1,4-manner to
afford a zinc enolate 7 bearing an electrophilic site. Then the
formed enolate attacks the enone unit intramolecularly in a 1,2-
manner in turn, and gives the cyclohexene derivative 4. This major
product 4 has the most stable conformation, in which all large
substituents occupy equatorial positions. The cyclization to 4
shoud be reversible. In order to achieve this reaction efficiently, an
organozinc reagent should perform a transmetalation prior to its
direct nucleophilic attack to the substrate. The dianionic character
of gem-dizinc 1 would promote the umpolung step; thus, the dizinc
1 was the most suitable reagent for this reaction which has ideal
reactivity.
General procedure for preparation of cyclohexene derivatives 4
The reaction was performed in a 20 mL round-bottomed flask
filled with argon gas. Bis(iodozincio)methane (1, 0.5 mmol, 0.5 M
in THF) was added to the solution of g-acyloxy-a,b-unsaturated
ketone (2, 0.5 mmol) in THF (5.0 mL) in the presence of 3
mol% of Pd(PPh3)4. Then the mixture was stirred at 25 ◦C for
1.5–6 h. After an addition of saturated aqueous ammonium
chloride solution, the mixture was extracted with ethyl acetate.
The combined organic layers were washed with brine, dried over
sodium sulfate, and concentrated in vacuo. Purification by a flash
silica gel column chromatography gave the pure corresponding
cyclohexene derivative 4.
((1R*,5R*,6S*)-6-Benzoyl-5-hydroxy-5-phenylcyclohex-3-enyl)-
methyl acetate (4a). Yield: 77%, white solid. TLC: Rf 0.21
(hexane–ethyl acetate = 3 : 1). Mp. 135.5–136.0 ◦C. 1H NMR
(500 MHz, CDCl3) d 7.51–7.47 (m, 2H), 7.43–7.39 (m, 1H),
7.34–7.31 (m, 2H), 7.26–7.21 (m, 2H), 7.20–7.14 (m, 2H),
7.09–7.04 (m, 1H), 6.07 (ddd, J = 10.0, 5.0, 2.0 Hz, 1H), 5.88
(ddd, J = 10.0, 2.0, 2.0 Hz, 1H), 5.17 (s, 1H), 3.92 (d, J = 12.0 Hz,
1H), 3.89 (d, J = 4.5 Hz, 2H), 3.00–2.90 (m, 1H), 2.43 (dddd,
J = 18.5, 5.0, 5.0, 2.0 Hz, 1H), 2.26 (dddd, J = 18.5, 11.0, 2.0,
2.0 Hz, 1H), 1.71 (s, 3H). 13C NMR (125 MHz, CDCl3) d 206.8,
170.4, 145.9, 138.0, 133.4, 132.5, 128.3, 128.3, 128.1, 127.9, 127.0,
125.2, 73.6, 65.9, 53.3, 34.0, 29.0, 20.4. IR (KBr): 3447, 1742,
1653, 1447, 1362, 1248, 1227, 1049, 698 cm-1. HRMS Calcd for
C20H18O4: M+, 350.1518. Found: m/z 350.1517.
Experimental section
Preparation of bis(iodozincio)methane (1)
A mixture of pure zinc dust (150 mmol), diiodomethane (1.0
mmol), and PbCl2 (0.005 mmol) in THF (5.0 mL) was sonicated for
1 h in an ultrasonic cleaner bath under Ar. When pyrometallurgy
zinc dust was used instead of pure zinc, it is not necessary to add
PbCl2. Both of pure zinc and pyrometallurgy zinc are commercially
available. To the mixture, diiodomethane (50 mmol) in THF (45
mL) was added dropwise over 30 min at 0 ◦C with vigorous stirring.
The mixture was stirred for 4 h at 25 ◦C. After the stirring was
stopped, the reaction vessel was allowed to stand undisturbed
for several hours. Excess zinc was separated by sedimentation.
1H NMR spectra of the obtained supernatant showed a broad
singlet at -1.2 ppm at 0 ◦C, which corresponded to the methylene
proton of 1. The supernatant was used for the further reaction
as a solution of 1 in THF (0.4–0.5 M). Bis(iodozincio)methane
in THF can be kept unchanged at least for a month in a sealed
reaction vessel.
((1R*,5S*,6S*)-6-Benzoyl-5-hydroxy-5-phenylcyclohex-3-enyl)-
methyl acetate (4¢a). Yield: 5.5%, colorless oil. TLC: Rf 0.32
(hexane–ethyl acetate = 3 : 1). 1H NMR (500 MHz, CDCl3) d 8.04–
7.96 (m, 2H), 7.61–7.55 (m, 1H), 7.50–7.43 (m, 3H), 7.40–7.33 (m,
4H), 6.01 (ddd, J = 10.0, 5.0, 2.5 Hz, 1H), 5.79 (ddd, J = 10.0,
2.0, 2.0 Hz, 1H), 4.61 (bs, 1H), 4.27 (d, J = 5.5 Hz, 2H), 3.15 (d,
J = 12.0 Hz, 1H), 3.0–2.9 (m, 1H), 2.48 (dddd, J = 18.5, 5.0, 5.0,
2.0 Hz, 1H), 2.22 (dddd, J = 18.5, 11.0, 2.5, 2.0 Hz, 1H), 1.67 (s,
3H). 13C NMR (125 MHz, CDCl3) d 215.2, 166.2, 145.6, 133.3,
132.2, 129.7, 129.5, 128.5, 128.4, 128.2, 127.2, 125.2, 73.0, 66.7,
59.8, 34.1, 33.4, 28.7. IR (neat): 3458, 3028, 2361, 1715, 1694,
1601, 1449, 1269, 1115, 1001, 764, 712, 469 cm-1. HRMS Calcd
for C20H18O4: M+, 350.1518. Found: m/z 350.1516.
((1R*,5R*,6S*)-6-(2-Naphthoyl)-5-hydroxy-5-(naphthalen-2-yl)-
cyclohex-3-enyl)methyl acetate (4b). Yield: 72%, white so◦lid.
TLC: Rf 0.18 (hexane–ethyl acetate = 3 : 1). Mp. 155.0–156.0 C.
1H NMR (500 MHz, CDCl3) d 7.90 (dd, J = 12.5, 2.0 Hz,
2H), 7.72–7.58 (m, 7H), 7.51–7.46 (m, 2H), 7.42–7.38 (m, 1H),
7.36–7.28 (m, 2H), 6.14 (ddd, J = 10.0, 5.0, 2.5 Hz, 1H), 5.96
(ddd, J = 10.0, 2.5, 2.0 Hz, 1H), 5.44 (s, 1H), 4.22 (d, J = 11.5 Hz,
1H), 3.94 (d, J = 4.5 Hz, 2H), 3.12–3.02 (m, 1H), 2.50 (dddd, J =
18.5, 5.0, 5.0, 2.0 Hz, 1H), 2.37 (dddd, J = 18.5, 11.0, 2.5, 2.5 Hz,
1H), 1.65 (s, 3H).13C NMR (125 MHz, CDCl3) d 206.6, 170.4,
143.2, 135.5, 135.1, 133.0, 132.5, 132.3, 131.9, 130.2, 129.4, 128.7,
128.5, 128.2, 128.1, 128.0, 127.5, 127.3, 126.7, 126.0, 125.7, 124.2,
123.6, 123.2, 74.0, 65.9, 52.9, 34.2, 29.1, 20.4. IR (KBr): 3408,
1740, 1653, 1622, 1362, 1233, 1038, 827, 748 cm-1. HRMS Calcd
for C20H18O4: M+, 450.1831. Found: m/z 450.1840.
Preparation of (E)-4-oxo-4-phenylbut-2-enyl acetate (2a)
The substrate 2a is easily obtained by an acetylation of the
corresponding g-hydroxy-a,b-unsaturated ketone, (E)-4-hydroxy-
1-phenylbut-2-en-1-one, which is obtained in 4 steps from ben-
zaldehyde in 49% overall yield by our reported procedure.1
To a solution of (E)-4-hydroxy-1-phenylbut-2-en-1-one (10
mmol) in dichloromethane (10 mL), pyridine (24 mmol), acetic
anhydride (12 mmol), and N,N-dimethyl-4-aminopyridine (0.5
mmol) were added subsequently and stirred for 12 h at 25 ◦C. A
saturated aqueous solution of ammonium chloride was added to
the reaction mixture, and then the mixture was extracted with ethyl
acetate. The combined organic layers were washed with brine,
dried over sodium sulfate, and concentrated in vacuo. After a
purification by a flash silica gel column chromatography (hexane–
ethyl acetate = 5 : 1), the pure acetate 2a was isolated in 96%
yield.
((1R*,5R*,6S*)-5-Hydroxy-6-(4-methylbenzoyl)-5-p-tolylcyclo-
hex-3-enyl)methyl acetate (4c). Yield: 65%, white solid. TLC: Rf
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0.31 (hexane–ethyl acetate = 3 : 1). Mp. 136.0–137.0 ◦C. 1H NMR
(500 MHz, CDCl3) d 7.44 (ddd, J = 8.0, 1.5, 1.5 Hz, 2H), 7.21
(ddd, J = 8.0, 2.0, 2.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 6.98
(d, J = 8.0 Hz, 2H), 6.02 (ddd, J = 10.0, 5.0, 2.5 Hz, 1H), 5.84
(ddd, J = 10.0, 2.5, 2.0 Hz, 1H), 5.34 (s, 1H), 3.87 (d, J = 11.5 Hz,
1H), 3.86 (d, J = 5.0 Hz, 2H), 2.98–2.88 (m, 1H), 2.40 (dddd, J =
18.5, 5.0, 5.0, 2.0 Hz, 1H), 2.31 (s, 3H), 2.23 (dddd, J = 18.5, 11.0,
2.5, 2.5 Hz, 1H), 2,19 (s, 3H), 1.74 (s, 3H). 13C NMR (125 MHz,
CDCl3) d 206.4, 170.4, 144.4, 143.1, 136.3, 135.5, 132.8, 128.9,
128.7, 128.1, 127.9, 125.1, 73.5, 65.9, 52.9, 34.0, 28.9, 21.5, 20.8,
20.4. IR (KBr): 3457, 1738, 1647, 1605, 1362, 1238, 1032, 812 cm-1.
HRMS Calcd for C20H18O4: M+, 378.1831. Found: m/z 378.1827.
((1R*,5R*,6S*)-5-Hydroxy-5-phenethyl-6-(3-phenylpropanoyl)-
cyclohex-3-enyl)methyl acetate (4f). Yield: 48%, colorless oil.
TLC: Rf 0.18 (hexane–ethyl acetate = 3 : 1). 1H NMR (500 MHz,
CDCl3) d 7.30–7.22 (m, 4H), 7.21–7.16 (m, 2H), 7.16–7.12 (m,
2H), 7.12–7.08 (m, 2H), 5.88 (ddd, J = 10.0, 5.0, 2.5 Hz, 1H),
5.77 (ddd, J = 10.0, 2.5, 2.0 Hz, 1H), 3.98 (dd, J = 11.5, 4.5 Hz,
1H), 3.89 (dd, J = 11.5, 4.5 Hz, 1H), 3.86 (s, 1H), 2.97–2.88 (m,
2H), 2.87–2.77 (m, 3H), 2.73–2.59 (m, 3H), 2.25 (dddd, J = 18.5,
5.0, 5.0, 2.0 Hz, 1H), 2.04 (s, 3H), 1.95 (dddd, J = 18.5, 11.5, 2.5,
2.5 Hz, 1H), 1.80 (ddd, J = 13.5, 11.5, 5.0 Hz, 1H), 1.70 (ddd,
J = 13.5, 11.5, 6.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) d 216.4,
170.5, 141.6, 140.6, 130.4, 128.9, 128.5, 128.5, 128.3, 128.3, 126.2,
126.0, 71.5, 65.9, 55.2, 48.8, 43.0, 35.2, 30.6, 28.8, 28.8, 20.8. IR
(neat): 3464, 2930, 1742, 1694, 1233, 1036, 700 cm-1. HRMS Calcd
for C20H18O4: M+, 406.2144. Found: m/z 406.2144.
((1R*,5R*,6S*)-5-Hydroxy-6-(4-methoxybenzoyl)-5-(4-metho-
xyphenyl)cyclohex-3-enyl)methyl acetate (4d). Yield: 52%, white
solid. TLC: Rf 0.21 (hexane–ethyl acetate = 3 : 1). Mp. 110.0–
◦
((1R*,5S*,6S*)-5-Hydroxy-5-phenethyl-6-(3-phenylpropanoyl)-
cyclohex-3-enyl)methyl acetate (4¢f). Yield: 23%, colorless oil.
TLC: Rf 0.14 (hexane–ethyl acetate = 3 : 1). 1H NMR (500 MHz,
CDCl3) d 7.32–7.26 (m, 4H), 7.23–7.18 (m, 4H), 7.18–7.13 (m,
2H), 5.87 (ddd, J = 10.0, 5.0, 2.0 Hz, 1H), 5.77 (ddd, J = 10.0, 2.5,
2.0 Hz, 1H), 4.05 (dd, J = 11.5, 5.0 Hz, 1H), 3.97 (dd, J = 11.5,
5.0 Hz, 1H), 3.76 (s, 1H), 2.96 (t, J = 7.5 Hz, 2H), 2.75 (d, J =
12.0 Hz, 1H), 2.71–2.58 (m, 5H), 2.19 (dddd, J = 18.0, 5.0, 5.0,
2.0 Hz, 1H), 2.17 (s, 3H), 1.91–1.74 (m, 3H). 13C NMR (125 MHz,
CDCl3) d 215.6, 172.5, 141.7, 140.2, 130.4, 128.9, 128.6, 128.5,
128.3, 128.3, 126.4, 126.0, 71.3, 66.0, 55.7, 43.0, 35.7, 34.1, 33.1,
30.8, 30.6, 28.8. IR (neat): 3458, 2930, 1736, 1694, 1497, 1360,
1161, 700 cm-1. HRMS Calcd for C20H18O4: M+, 406.2144. Found:
m/z 406.2136.
1
110.5 C. H NMR (500 MHz, CDCl3) d 7.56 (ddd, J = 10.0,
2.5, 2.5 Hz, 2H), 7.24 (ddd, J = 10.0, 2.5, 2.5 Hz, 2H), 6.73 (ddd,
J = 9.0, 2.0, 2.0 Hz, 2H), 6.70 (ddd, J = 9.0, 2.5, 2.5 Hz, 2H), 6.02
(ddd, J = 10.0, 5.0, 2.5 Hz, 1H), 5.83 (ddd, J = 10.0, 2.0, 2.0 Hz,
1H), 5.40 (s, 1H), 3.88–3.81 (m, 3H), 3.80 (s, 3H), 3.67 (s, 3H),
2.97–2.86 (m, 1H), 2.41 (dddd, J = 18.5, 5.0, 5.0, 2.0 Hz, 1H),
2.23 (dddd, J = 18.5, 11.0, 2.5, 2.0 Hz, 1H), 1.78 (s, 3H). 13C NMR
(125 MHz, CDCl3) d 204.9, 170.5, 163.9, 158.3, 138.3, 132.8, 130.8,
130.5, 128.0, 126.3, 113.5, 113.4, 73.2, 66.0, 55.4, 55.1, 52.5, 34.0,
28.9, 20.5. IR (KBr): 3412, 2359, 1738, 1653, 1508, 1260, 1238,
1180, 1032, 847 cm-1. HRMS Calcd for C20H18O4: M+, 410.1729.
Found: m/z 410.1724.
((1R*,5S*,6S*)-5-Hydroxy-6-(4-methoxybenzoyl)-5-(4-metho-
xyphenyl)cyclohex-3-enyl)methyl acetate (4¢d). Yield: 15%, white
solid. TLC: Rf 0.30 (hexane–ethyl acetate = 3 : 1). Mp. 111.0–
((1R*,5R*,6S*)-6-Benzoyl-5-hydroxy-5-phenylcyclohex-3-enyl)-
methyl isobutyrate (4g). Yield: 75%, white solid. TLC: Rf
0.25 (hexane–ethyl acetate = 3 : 1). Mp. 107.0–107.5 ◦C. 1H
NMR (500 MHz, CDCl3) d 7.48–7.44 (m, 2H), 7.42–7.37 (m,
1H), 7.35–7.30 (m, 2H), 7.24–7.19 (m, 2H), 7.19–7.14 (m, 2H),
7.09–7.04 (m, 1H), 6.07 (ddd, J = 10.0, 5.0, 2.5 Hz, 1H), 5.88
(ddd, J = 10.0, 2.5, 2.5 Hz, 1H), 5.13 (s, 1H), 3.94 (dd, J = 11.5,
4.0 Hz, 1H), 3.90 (d, J = 12.0 Hz, 1H), 3.86 (dd, J = 11.5, 5.0 Hz,
1H), 3.01–2.90 (m, 1H), 2.43 (dddd, J = 18.5, 5.0, 5.0, 2.5 Hz,
1H), 2.25 (dddd, J = 18.5, 10.5, 2.5, 2.5 Hz, 1H), 2.23 (sept, J =
7.0 Hz, 1H), 0.96 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H).
13C NMR (125 MHz, CDCl3) d 206.8, 176.5, 145.9, 137.9, 133.4,
132.4, 128.4, 128.3, 128.1, 127.9, 127.0, 125.2, 73.6, 65.7, 53.5,
34.2, 33.7, 28.9, 18.8, 18.6. IR (KBr): 3428, 1734, 1651, 1449,
1339, 1244, 1152, 1055, 691 cm-1. HRMS Calcd for C20H18O4: M+,
378.1831. Found: m/z 378.1842.
◦
1
112.5 C. H NMR (500 MHz, CDCl3) d 7.94 (ddd, J = 9.0,
2.5, 2.5 Hz, 2H), 7.28 (ddd, J = 10.0, 2.0, 2.0 Hz, 2H), 6.93 (ddd,
J = 9.0, 2.0, 2.0 Hz, 2H), 6.87 (ddd, J = 9.0, 2.5, 2.5 Hz, 2H), 5.97
(ddd, J = 10.0, 5.0, 2.0 Hz, 1H), 5.76 (ddd, J = 10.0, 2.5, 1.5 Hz,
1H), 4.59 (s, 1H), 4.23 (d, J = 5.0 Hz, 2H), 3.86 (s, 3H), 3.80 (s,
3H), 3.10 (d, J = 12.0 Hz, 1H), 3.0–2.9 (m, 1H), 2.44 (dddd, J =
18.5, 5.0, 5.0, 1.5 Hz, 1H), 2.18 (dddd, J = 18.5, 11.5, 2.5, 2.0 Hz,
1H), 1.71 (s, 3H). 13C NMR (125 MHz, CDCl3) d 215.6, 166.0,
163.6, 158.6, 137.7, 132.4, 131.6, 128.1, 126.3, 122.0, 113.8, 113.7,
72.7, 66.4, 59.8, 55.4, 55.2, 34.3, 33.5, 28.7. IR (KBr): 3366, 2359,
1715, 1684, 1607, 1508, 1271, 1252, 1169, 1026, 770 cm-1. HRMS
Calcd for C20H18O4: M+, 410.1729. Found: m/z 410.1731.
((1R*,5R*,6S*)-6-(4-Bromobenzoyl)-5-(4-bromophenyl)-5-
hydroxycyclohex-3-enyl)methyl acetate (4e). Yield: 80%, white
solid. TLC: Rf 0.18 (hexane–ethyl acetate = 3 : 1). Mp. 126.0–
126.5 ◦C. 1H NMR (500 MHz, CDCl3) d 7.45–7.38 (m, 4H), 7.30
(ddd, J = 8.5, 2.5, 2.5 Hz, 2H), 7.19 (ddd, J = 8.5, 2.0, 2.0 Hz,
1H), 6.06 (ddd, J = 10.0, 5.0, 2.0 Hz, 1H), 5.80 (ddd, J = 10.0, 2.5,
2.0 Hz, 1H), 4.99 (s, 1H), 3.90 (dd, J = 11.5, 4.5 Hz, 1H), 3.87 (dd,
J = 11.5, 4.5 Hz, 1H), 3.80 (d, J = 11.5 Hz, 1H), 2.97–2.87 (m, 1H),
2.42 (dddd, J = 18.5, 5.0, 5.0, 2.0 Hz, 1H), 2.24 (dddd, J = 18.5,
11.5, 2.5, 2.0 Hz, 1H), 1.77 (s, 3H). 13C NMR (125 MHz, CDCl3) d
205.1, 170.2, 144.9, 136.4, 131.9, 131.8, 131.3, 129.4, 129.3, 128.7,
127.1, 121.2, 73.4, 65.7, 53.1, 34.0, 28.8, 20.5. IR(KBr):3648, 1738,
1651, 1398, 1234, 1011, 819 cm-1. HRMS Calcd for C20H18O4: M+,
505.9728. Found: m/z 505.9724.
((1R*,5R*,6S*)-6-Benzoyl-5-hydroxy-5-phenylcyclohex-3-enyl)-
methyl benzoate (4h). Yield: 76%, white solid. TLC: Rf 0.24
(hexane–ethyl acetate = 3 : 1). Mp. 119.5–120.0 ◦C. 1H NMR
(500 MHz, CDCl3) d 7.78–7.74 (m, 2H), 7.54–7.50 (m, 1H),
7.46–7.42 (m, 2H), 7.39–7.33 (m, 4H), 7.31–7.26 (m, 1H),
7.20–7.15 (m, 2H), 7.10–7.04 (m, 3H), 6.10 (ddd, J = 10.0, 5.0,
2.5 Hz, 1H), 5.91 (ddd, J = 10.0, 2.5, 2.0 Hz, 1H), 5.29 (s, 1H),
4.21 (dd, J = 11.5, 5.0 Hz, 1H), 4.11 (dd, J = 11.5, 4.5 Hz, 1H),
3.98 (d, J = 11.5 Hz, 1H), 3.16–3.07 (m, 1H), 2.54 (dddd, J =
18.5, 5.5, 5.0, 2.0 Hz, 1H), 2.35 (dddd, J = 18.5, 11.0, 2.5, 2.5 Hz,
1H). 13C NMR (125 MHz, CDCl3) d 206.8, 166.0, 145.9, 137.7,
133.4, 132.9, 132.5, 129.6, 129.5, 129.4, 128.3, 128.2, 128.1, 127.9,
1392 | Org. Biomol. Chem., 2011, 9, 1389–1393
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127.0, 125.2, 73.7, 66.3, 53.5, 34.5, 29.1. IR (KBr): 3480, 1717,
1647, 1449, 1273, 1233, 1113, 704, 691 cm-1. HRMS Calcd for
C20H18O4: M+, 412.1675. Found: m/z 412.1677.
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White solid. (enol form) 1H NMR (500 MHz, CDCl3) d 7.90–7.87
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Conclusions
We have demonstrated a novel tandem reaction initiated by a
1,4-addition of the zinc reagent prepared from an umpolung
method. Using the umpolung of p-allylpalladium species by
bis(iodozincio)methane (1), we could prepare the zinc dienolate
to perform this tandem reaction efficiently. The cyclic product 4
was obtained with quite high diastereoselectivity, and therefore
this reaction would be one of the useful methods to construct
multiple adjacent stereocenters in a single process. This reaction
required the use of a reagent having a certain level of reactivity
with superb balance, since there are many functional groups in
both the substrates 2 and the products 4. On this point, the gem-
dizinc 1 was an excellent reagent and we could show another useful
transformation that utilized the characteristic feature of 1.
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Notes and references
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