One-pot asymmetric conjugate addition-trapping of zinc enolates by activated electrophiles

Article abstract of DOI:10.1021/jo060814j

The copper-catalyzed asymmetric conjugate addition of dialkyl zinc leads to homochiral zinc enolates. These intermediates were trapped in situ with activated allylic electrophiles, without the need of additional palladium catalysis. High trans selectivity

Full text of DOI:10.1021/jo060814j

One-Pot Asymmetric Conjugate Addition-Trapping of Zinc
Enolates by Activated Electrophiles
Xavier Rathgeb, Se´bastien March, and Alexandre Alexakis*
Department of Organic Chemistry, UniVersity of GeneVa, 30 quai Ernest-Ansermet,
GeneVa 4, Switzerland CH-1211
alexandre.alexakis@chiorg.unige.ch
ReceiVed April 18, 2006
The copper-catalyzed asymmetric conjugate addition of dialkyl zinc leads to homochiral zinc enolates.
These intermediates were trapped in situ with activated allylic electrophiles, without the need of additional
palladium catalysis. High trans selectivity (85/15 to 100/0) and excellent enantioselectivities (up to 99%)
could be attained. The functionalized nature of the electrophiles makes the new synthons potential
candidates for further elaboration.
Introduction
tion can be done by addition of halogenating agents.13 Alkyl
iodides react under forcing conditions (10-20 equiv and
HMPA),14,15 whereas allylic acetates react with added Pd
catalyst.10,11 Allyl bromide itself reacts very sluggishly without
Pd catalysis.
The copper-catalyzed conjugate addition is a very useful
reaction to control carbon-carbon bond formation on the â
position of enones.1-3 Recent years have seen tremendous
advances in the asymmetric variant of this reaction with ee’s
greater than 99%, using as little as 0.5 mol % of copper salt
and 1 mol % of chiral ligand.4,5 When the primary organome-
tallic is a dialkyl zinc species, these reactions end up with the
formation of a zinc enolate that is, usually, simply hydrolyzed.
However, these enolates may be trapped with a variety of
electrophiles, thus creating a second stereocenter, R to the
carbonyl group. Although the concept of conjugate addition-
enolate trapping is not new6 and has been extensively applied
to the synthesis of natural products,7 it has scarcely been used
with the particularly poorly reactive homochiral zinc enolates.8
Thus, in addition to silylation,9 aldol reactions may be performed
with aldehydes,10,11 acetals, or orthoformate,12 and R-halogena-
In the course of our studies on the reactivity of zinc
enolates,16,17 we considered that more reactive allylic halides
could be good candidates for this trapping. Particularly, we
thought that Pd catalysis might not be needed, the present copper
catalyst being enough. The chosen substrates all share the same
characteristic: an electron-withdrawing group in vinylic position
and a leaving group in allylic position (Figure 1). Although the
reaction proceeds probably by a conjugate addition-elimination
mechanism, they are usually considered as allylic substitu-
tions.18,19
(10) Noyori, R.; Kitamura, M.; Miki, T.; Nakano, K. Bull. Chem. Soc.
Jpn. 2000, 73, 999-1014.
* To whom correspondence should be addressed. Fax: +41 22 379 32 15.
(1) Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(2) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061.
(3) Krause, N. Modern Organocopper Chemistry; Wiley-VCH: Wein-
heim, 2002.
(4) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221-3226.
(5) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353.
(6) Boeckman, R. K., Jr. J. Org. Chem. 1973, 38, 4450-4452.
(7) Chapdelaine, M. J.; Hulce, M. Org. React. 1990, 38, 225-653.
(8) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354-366.
(9) Alexakis, A.; Knopff, O. Org. Lett. 2002, 4, 3835-3837.
(11) Noyori, R.; Kitamura, M.; Miki, T.; Nakano, K. Tetrahedron Lett.
1996, 37, 5141-5144.
(12) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J. Am. Chem. Soc.
2001, 123, 4358-4359.
(13) Li, K.; Alexakis, A. Tetrahedron Lett. 2005, 46, 5823-5826.
(14) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755-756.
(15) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 779-781.
(16) Alexakis, A.; March, S. J. Org. Chem. 2002, 67, 8753-8757.
(17) Li, K.; Alexakis, A. Tetrahedron Lett. 2005, 46, 8019-8022.
10.1021/jo060814j CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/28/2006
J. Org. Chem. 2006, 71, 5737-5742
5737

Rathgeb et al.
TABLE 2. Trapping in the Presence of Additional Catalysts
entry
Ex
catalyst
8c
9c
unreacted Exc
10c
1a
2b
3b
4b
4
5
2
2
2% Pd
2% Pd
2% Pd
2% Ni
44%
36%
9%
15%
7%
28%
28%
41%
57%
41%
49%
trace
trace
22%
19%
4%
FIGURE 1. Electrophiles used to trap zinc enolates.
a Trapping proceeds at -30 °C. b Trapping proceeds at room temperature.
TABLE 1. Conjugate Addition-Trapping with Electrophiles
c 1H NMR or 31P NMR ratio.
entry
Ex
trapping conditions (°C)
8
9
10
1
2
3
4
5
6
7
8
1
1
2
3
3
4
4
5
+20
-30
-30
+20
-30
+20
-30
+20
51%
82%
13%
36%
12%
45%
36%
11%
49%
18%
56%
64%
77%
55%
64%
10%
0%
0%
31%
0%
11%
0%
0%
It possibly could be argued that palladium catalysis may help
in a better discrimination of the transfer of the ethyl group versus
the enolate. To check this point, we repeated some experiments
(according to Scheme 1) with added Pd(PPh3)4 or Ni(acac)2, 2
mol %, with trapping at -30 °C. As can be seen from Table 2
there is indeed some improvement with substrates 4 and 5 but
not with 2, with either Pd or Ni.
78%
As the most interesting alkyl group in natural product
synthesis is the methyl group, we tested the same reaction with
Me2Zn (Scheme 3). An additional advantage in such a reaction
would be the differential reactivity on the mixed zinc enolate.
While the reactivity of the enolate part would essentially be
the same as previously, the reactivity of the Me group is
notoriously lower than that of the Et group.4,11 The results are
shown in Table 3. Indeed, as compared to the results with Et2-
Zn (Tables 1 and 2), the ratio of the desired product 12 versus
the product of the methyl transfer 13 is significantly better. Thus
12a was obtained in 85% yield instead of 51% for 8a. The same
trend is observed with the other electrophiles. Only substrate 5
was not tested, as its reactivity was much poorer than that of
its sister substrate 4. We have also tested the influence of Pd
catalysis (with Pd(PPh3)4). Although larger amount of unreacted
electrophile were observed, the ratio of 12 versus 13 is greatly
improved, particularly for substrates 2, 3, and 4 (compare entries
2 and 6, 2 and 7, 4 and 8).
As our goal was to avoid additional catalyst, we sought a
simpler solution. The obtained products 8 and 9, and 12 and
13, are easily separable on column chromatography. Therefore,
we just added more of the electrophile, 1.5-2.4 equiv instead
of 1.2. Another modification was done in order to improve the
enantioselectivity of the first step, the asymmetric conjugate
addition. This was to replace Cu(OTf)2 by copper thiophene
carboxylate (CuTC).20,25,26 In addition, we also tested cyclo-
heptenone 15 as starting enone. The results obtained according
to Scheme 4 are shown in Table 4.
In all cases, the isolated yield of the alkylated product is good.
Only with the phosphonate derivatives 8d and 12d were the
products not fully separated from the ethylated or methylated
products 9d or 13d. The enantioselectivity was measured on
the final product, and it is excellent in all cases. In fact, the
true enantiodetermining step is the conjugate addition. The other
very important point is the trans/cis ratio of the final product.
Although the most thermodynamically stable isomer, the selec-
tive formation of the trans product results from the allylation
from the least sterically hindered face of the enolate. This is
agreement with all previous results of the literature on such
tandem conjugate addition-enolate trapping.7
Results and Discussion
The synthesis of 1-5 was done according to known proce-
dures or by modifications of described ones (see Experimental
Section for details). The asymmetric conjugate addition was first
performed under our usual conditions4,16,20,21 (1.2 equiv of Et2-
Zn, 1% CuOTf2, 2% L1, Et2O, -30 °C), then the electrophiles
1-5 were added (1.2 equiv), and the mixture was either
maintained at -30 °C (15 h) or warmed to room temperature
for 6 h.
As anticipated, the conversion of the conjugate addition is
quantitative. The resulting zinc enolate is reactive enough in
most cases, as can be seen by the amount of the hydrolyzed
conjugate adduct 10 left (see Table 1). Even at -30 °C,
substrates 1 and 4 react quantitatively, without any metal catalyst
other than the present copper salt. Only pivalate 5 is much less
reactive than its corresponding bromide 4. However, the most
striking observation was the large amount of ethyl adducts 9.
In the previously reported Pd-catalyzed allylations with allyl
acetate, such products were never noticed, probably because of
the volatility of the resulting 1-pentene.10,11 The ratio of the
desired product 8 versus the ethyl adduct 9 varies with the
temperature of the trapping reaction. Except for 1 (entries 1
and 2), low temperature has a detrimental effect. Changing the
solvent of the second step from Et2O to CH2Cl2, toluene, or
THF did not alter fundamentally these results.
The large amounts of undesired product 9 could not result
only from the 20% excess of Et2Zn used. Indeed, a control
experiment with 0.8 equiv of Et2Zn was performed, in which
case no Et2Zn is anymore available (Scheme 2). The fact that
43% of 9d is still present could only be explained by the
respective reactivity, on 7, of the ethyl group and the enolate,
both linked to Zn.10,11 This is rather unusual, as on the trapping
with aldehydes or acetals, to form the aldol product, the transfer
of the ethyl group was never observed.5,10-12,22-24
(18) Borner, C.; Goldsmith, P. J.; Woodward, S.; Gimeno, J.; Gladiali,
S.; Ramazzotti, D. Chem. Commun. 2000, 2433-2434.
(19) Goldsmith, P. J.; Teat, S. J.; Woodward, S. Angew. Chem., Int. Ed.
2005, 44, 2235-2237.
(20) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem.
Soc. 2002, 124, 5262-5263.
(21) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
Benhaim, C. Synlett 2001, 9, 1375-1378.
(22) Feringa, B. L.; Pineschi, M.; Arnolds, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620-2623.
(23) Feringa, B. L.; Arnold, L. A.; Naasz, R.; Minnaard, A. J. J. Am.
Chem. Soc. 2001, 123, 5841-5842.
(24) Feringa, B. L.; Mandoli, A.; Arnold, L. A.; de Vries, A. H. M.;
Salvadori, P. Tetrahedron: Asymmetry 2001, 12, 1929-1937.
(25) Alexakis, A.; Polet, D.; Benhaim, C.; Rosset, S. Tetrahedron:
Asymmetry 2004, 15, 2199-2203.
(26) Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org. Chem. 2004,
69, 5660-5667.
5738 J. Org. Chem., Vol. 71, No. 15, 2006

Conjugate Addition-Trapping of Zinc Enolates
SCHEME 1. Conjugate Addition of Diethyl Zinc-Trapping with Electrophiles
SCHEME 2. Control Experiment with Default of Et2Zn
SCHEME 3. Conjugate Addition of Dimethyl Zinc-Trapping with Electrophiles
TABLE 3. Addition of Me2Zn-Trapping with 1-4
TABLE 4. Results According to Scheme 4
entry
Ex
catalyst
12c
13c
unreacted Exc
entry
n
R2Zn Ex (equiv) product yielda trans/cisb
eec
1a
2b
3a
4a
5a
6b
7a
8a
1
2
3
4
1
2
3
4
85%
37%
24%
52%
88%
65%
32%
62%
15%
47%
29%
48%
12%
14%
21%
11%
0%
16%
47%
trace
0%
21%
47%
27%
1
2
3
4
5
6
7
8
9
10
1
1
1
1
1
1
1
1
2
2
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Me2Zn
Me2Zn
Me2Zn
Me2Zn
Et2Zn
Et2Zn
1 (1.5)
2 (2.4)
3 (2.4)
4 (2.4)
1 (1.5)
2 (2.4)
3 (2.4)
4 (2.4)
1 (1.5)
2 (2.4)
8a
8b
8c
72%
70%
60%
65%g
80%
74%
73%
67%g
68%
72%
95/5
91/9
99.1%
98.7%
98.7%
>98%d
98.5%
98.9%
99.1%
>98%d
90.8%
94.6%
78/22f
88/12
90/10
94/6
8d
2% Pd
2% Pd
2% Pd
2% Pd
12a
12b
12c
12d
15a
15b
89/11
nd
>98%
>98%
a Trapping proceeds at -30 °C. b Trapping proceeds at room temperature.
c 1H NMR or 31P NMR ratio.
a Isolated yield. b Determined by GC-MS. c Determined by chiral GC
or SFC on the final products for major dia. d Determined on the conjugate
addition step. f Measured by 1H NMR. g Not fully separated from 9d or
13d.
SCHEME 4. Conjugate Addition-Trapping with
Electrophiles under Optimized Conditions
lectivities are excellent, and the trans/cis ratio is very good.
The resulting functionalized compounds are useful synthetic
intermediates and their application in natural product synthesis
is under way.
Experimental Section
In summary, the allylic alkylation of the zinc enolates,
resulting from an asymmetric copper-catalyzed conjugate ad-
dition of dialkyl zinc, could be performed with activated allylic
substrates, in high yields and enantioselectivities. The reaction
is done as a one-pot procedure, and there is no need to have an
additional catalyst. The isolated yields are good, the enantiose-
2′-Nitro-2′-propen-1′-yl 2,2-dimethylpropanoate (1). Accord-
ing to the literature27,28 the following modifications were done. A
mixture of crude 2-nitropropane-1,3-diol (99.2 g, 813 mmol, 1
(27) Seebach, D.; Knochel, P. HelV. Chim. Acta 1984, 67, 261-283.
(28) Gensler, W. J.; Dheer, S. K. J. Org. Chem. 1981, 46, 4051-4057.
J. Org. Chem, Vol. 71, No. 15, 2006 5739

Rathgeb et al.
equiv) in 325 mL of CH2Cl2 was vigorously stirred and heated to
reflux. Pivaloyl chloride (250 mL, 2 mol, 2.5 equiv) was added in
3 h, and the HCl evolution was monitored by a bubbler. After the
end of introduction, the mixture was left still 1 h under reflux, then
it was cooled to room temperature, and left overnight with stirring.
The solvent and most of the rest of PivCl were removed by
evaporation to give crude 2′-nitrotrimethylene bis(2,2-dimethyl-
propanoate). All the crude was distilled under vacuum. PivCl and
PivOH distill first and then a mixture of PivOH, 1, and 2′-
nitrotrimethylene bis(2,2-dimethylpropanoate). A second distillation
and then a third distillation were done affording 94.50 g of pure
compound 1 (62% yield, bp 82-84 °C).
3-(5,5-Dimethylpropanoate)-2-propenyl-diethylphospho-
nate (5). According to the literature29 the following modifications
were done. Pivaloyl chloride (2.25 mL, 2 equiv) was added to a
solution of the corresponding allylic alcohol (1.75 g, 9 mmol, 1
equiv) in 5 mL of CH2Cl2 at room temperature. This mixture was
then heated to reflux for 2 h and cooled at room temperature. The
solvent and the excess of acid chloride were removed by evapora-
tion, and the crude product was purified by chromatography (silica,
AcOEt/MeOH, 9/1). This gave pure phosphonate 5 as a colorless
liquid (1.02 g, 41%). 1H NMR (400 MHz, CDCl3) δ 6.17 (dd, J )
22.5 Hz, J ) 1.2 Hz, 1H), 5.98 (dd, J ) 46.0 Hz, J ) 1.2 Hz, 1H),
4.69 (d, J ) 7.8 Hz, 2H,), 4.10 (m, 4H), 1.32 (t, 6H, J ) 7.1 Hz),
1.22 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 177.6, 134.8 (d, J )
177.2 Hz), 130.1 (d, J ) 6.6 Hz), 62.6 (d, J ) 18.1 Hz), 62.0 (d,
J ) 5.0 Hz), 38.8, 27.1, 16.2 (d, J ) 5.8 Hz). 31P NMR (162 MHz,
CDCl3) δ 16.78. IR (CDCl3) ν (cm-1) 2983, 1729, 1480, 1153
(large), 1028 (large), 973. LRMS (EI, 70 eV, m/z) 279 (M + H)+•,
193 (M - OPiv)+•, 57 (base peak). HRMS m/z M+• calcd for
C12H23O5P 278.1283, found 278.1264.
2H), 3.84 (m, 4H), 3.54 (m, 1H), 2.47 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 146.0, 134.0, 130.2, 129.0, 65.5, 26.4, 21.7. IR (CDCl3)
ν (cm-1) 3033, 2975, 2926, 2261, 1597, 1324 (large), 1150 (large).
LRMS (EI, 70, eV m/z) 356 (M+•), 277 (M - 79Br)+•, 275 (M -
81Br)+•, 91 (base peak). HRMS m/z (M - 79Br)+• calcd for
C10H12O2S81Br 276.9721, found 276.9715. (M - 81Br)+• calcd for
C10H12O2S79Br 274.9741, found 274.9761.
1-(9-Bromo-prop-8-ene-8-sulfonyl)-4-methyl-benzene (3). Ac-
cording to the literature30 the following modifications were done.
The above crude dibromo sulfone (5.4 g, 15 mmol, 1 equiv) was
dissolved in a mixture composed of 30 mL of dry ether and 20 mL
of dry CH2Cl2. Once the solution became clear, anhydrous NaOAc
(5.7 g, 69 mmol, 4.6 equiv) was added at room temperature and
1
the reaction was followed by H NMR. Once the conversion was
complete, the reaction mixture was filtered, and the solvent removed
by evaporation. This gave crude 3 in nearly quantitative yield and
was used without further purification. 1H NMR (400 MHz, CDCl3)
δ 7.77 (d, J ) 8.2 Hz, 2H), 7.35 (d, J ) 8.2 Hz, 2H), 6.59 (s, 1H),
6.21 (s, 1H), 4.09 (s, 2H), 2.45 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 147.1, 145.1, 135.6, 130.0, 128.5, 128.3, 25.2, 21.6. IR
(CDCl3) ν (cm-1) 2927, 2260, 1597, 1318 (large), 1149 (large).
LRMS (EI, 70, eV m/z) 276 (M+•), 274 (M+•), 195 (M - Br)+•, 91
(base peak). HRMS m/z (M - Br)+• calcd for C10H11O2S81Br
275.9643, found 275.9640; calcd for C10H11O2S79Br 273.9663,
found 273.9673.
General Procedure for Asymmetric Conjugate Addition with
Diethylzinc (ACA1). Dry ether (2 mL) was added to a dry round-
bottom flask containing copper thiophene carboxylate (CuTC) (3.8
mg, 0.02 mmol, 1%) and ligand (R,R)-L1 (18.8 mg, 0.04 mmol,
2%) under Ar. This mixture was stirred for 20 min at room
temperature and was cooled to -30 °C. After 20 min, diethylzinc
solution (1.0 M in hexane, 2.4 mL, 2.4 mmol, 1.2 equiv) was added,
followed 20 min later by 2-cyclohexenone 6 (193 µL, 2 mmol, 1
equiv) or 2-cycloheptenone 14 (220.2 mg, 2 mmol, 1 equiv). The
solution was stirred until complete consumption of the starting
material (usually 2-5 h).
General Procedure for Asymmetric Conjugate Addition with
Dimethylzinc (ACA2). Dry ether (2 mL) was added to a dry round-
bottom flask containing copper thiophene carboxylate (CuTC) (7.7
mg, 0.04 mmol, 2%) and ligand (R,R)-L1 (37.4 mg, 0.08 mmol,
4%) under Ar. This mixture was stirred for 20 min at room
temperature and was cooled to 0 °C. After 20 min, dimethylzinc
solution (2.0 M in toluene, 1.2 mL, 2.4 mmol, 1.2 equiv) was added,
followed 20 min later by 2-cyclohexenone 6 (193 µL, 2 mmol, 1
equiv). The solution was stirred until complete consumption of the
starting material (usually 2-5 h).
General Procedure for Quench, after Addition of the Elec-
trophiles 1-5. The mixture was hydrolyzed with HCl 10% and
ether. The aqueous layer was washed three times with ether. The
combined organic layers were dried with anhydrous MgSO4,
filtered, and concentrated in vacuo.
Allyl(p-tolyl)sulfane. According to the literature30 the following
modifications were done. p-Thiocresol (24.8 g, 200 mmol, 1 equiv)
was added at 50 °C with stirring to a solution of NaOEt (8.7 g of
Na, 200 mmol, 1 equiv in 112 mL of absolute ethanol). This mixture
was cooled to 0 °C, and allyl chloride (33 mL, 400 mmol, 2 equiv)
was added in 15 min. The reaction mixture was stirred for 1 h at
0 °C, then the water-ice bath was removed, and stirring was
continued for 19 h at room temperature. The solvent was evaporated
and the residue was taken up in Et2O and water. The organic layer
was washed with water dried with anhydrous MgSO4 and evapo-
rated. The product was purified by distillation under vacuum
affording allyl(p-tolyl)sulfane as a colorless liquid (30.0 g, 90%
yield). Bp (∼1 mmHg) 76-80 °C. 1H NMR (400 MHz, CDCl3) δ
7.29 (d, J ) 8.1 Hz, 2H), 7.12 (d, J ) 7.8 Hz, 2H), 5.89 (ddt, J )
9.8 Hz, J ) 7.1 Hz, J ) 7.1 Hz, 1H), 5.09 (m, 2H), 3.53 (d, J )
7.1 Hz, 2H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 136.4,
133.8, 132.0, 130.6, 129.5, 117.4, 37.8, 21.0. IR (neat) ν (cm-1
)
3080, 3019, 2979, 2919, 1636, 1492, 915, 801. LRMS (EI, 70, eV
m/z) 164 (M+•, base peak), 149, 123. HRMS m/z M+• calcd for
C10H12S 164.0660, found 164.0657.
1-(9,10-Dibromo-propane-8-sulfonyl)-4-methyl-benzene. Ac-
cording to the literature30 the following modifications were done.
To a solution of allyl(p-tolyl)thioether (26 g, 158 mmol, 1 equiv)
in 140 mL of CCl4 cooled to -10 °C was added in 2 h a solution
of bromine (8.13 mL, 158 mmol, 1 equiv) in 70 mL of CCl4,
keeping the temperature below -10 °C. The slightly orange solution
was allowed to reach room temperature and was added in 40 min
to a suspension of m-CPBA (93.9 g, 379 mmol, 2.4 equiv) in 800
mL of methylene chloride at -10 °C. The bath was then removed,
and stirring was continued for 24 h at room temperature. The
mixture was diluted with ether and saturated NaHCO3, and the
organic layer was washed several times with aqueous NaHCO3.
Drying with anhydrous MgSO4 and evaporation of the solvent gave
(3)-Ethyl-(2)-[(8-nitro)-allyl]-cyclohexanone (8a). Following
the general procedure ACA1 for the first step, the nitroolefin 1
(562.2 mg, 3.0 mmol, 1.5 equiv) was then added. The cooling bath
was removed, and the mixture was stirred for 6 h at room
temperature. The mixture was then quenched following the general
procedure. The product was purified by flash column chromatog-
raphy (silica, pentane/Et2O 8/2), to afford the desired compound
1
8a as a slightly yellow oil (305.6 mg, 72% yield). H NMR (400
MHz, CDCl3) δ 6.47 (s, 1H), 5.73 (s, 1H), 2.95 (dd, J ) 20.1 Hz,
J ) 12.8 Hz, 1H), 2.79 (dd, J ) 15.2 Hz, 2.3 Hz, 1H), 2.41 (m,
2H), 2.29 (m, 1H), 2.07 (m, 1H), 1.96 (m, 1H), 1.53 (m, 5H), 0.96
(t, J ) 10.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 211.5, 156.6,
119.8, 53.3, 45.7, 41.9, 29.7, 27.2, 26.1, 26.0, 10.3. IR (CDCl3) ν
(cm-1) 2971, 1735, 1706, 1526, 1147 (broad). LRMS (EI, 70 eV,
m/z) 211 M+•, 166 (M - NO2)+•, 57 (base peak). HRMS m/z (M
1
crude dibromo sulfone in nearly quantitative yield. H NMR (400
MHz, CDCl3) δ 7.79 (d, J ) 8.1 Hz, 2H), 7.39 (d, J ) 8.1 Hz,
- NO2)+• calcd for C11H17O 165.1279, found 165.1265. [R]20
)
D
(29) Knochel, P.; Normant, J. F. J. Organomet. Chem. 1986, 309, 1-23.
(30) Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 425-428.
+12.5 (c 1.00, CHCl3). ee of 99.1% was measured by chiral SFC
5740 J. Org. Chem., Vol. 71, No. 15, 2006

Conjugate Addition-Trapping of Zinc Enolates
with a chiracel AD column (program: 2% MeOH-5′ 1-10%, 200
bar, 2 mL/min, 30 °C). tR: 3.28 and 3.74.
Ethyl 2-((2-Methyl-6-oxocyclohexyl)methyl)acrylate (12b).
Following the general procedure ACA2 for the first step, the
bromoester 2 (925.1 mg, 4.8 mmol, 2.4 equiv) was then added.
The mixture was removed from the cooling bath and stirred for 3
h at room temperature. The mixture was then quenched following
the general procedure. The product was purified by flash column
chromatography (silica, pentane/Et2O 9/1) to afford the desired
compound 12b as a colorless liquid (331.3 mg, 74% yield). 1H NMR
(400 MHz, CDCl3) δ 6.16 (s, 1H), 5.62 (s, 1H), 4.18 (q, J ) 7.2
Hz, 2H), 2.71 (dd, J ) 14.5 Hz, J ) 9.4 Hz, 1H), 2.44 (d, J )
14.7 Hz, 1H), 2.31 (m, 3H), 2.01 (m, 1H), 1.87 (m, 1H), 1.96 (m,
2H), 1.49 (m, 1H), 1.29 (t, J ) 7.1 Hz, 3H), 1.11 (d, J ) 6.4 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 212.0, 167.2, 139.1, 126.3,
60.5, 56.6, 41.7, 39.7, 33.5, 29.0, 25.9, 20.5, 14.1. IR (CDCl3) ν
(cm-1) 2934, 1709, 1194, 1151 cm-1. LRMS (EI, 70 eV, m/z) 224
M+•, 209 (M - Me)+•, 111 (base peak). HRMS m/z M+• calcd for
Ethyl 2-((2-ethyl-6-oxocyclohexyl)methyl)acrylate (8b). Fol-
lowing the general procedure ACA1 for the first step, the bromoester
2 (929.1 mg, 4.8 mmol, 2.4 equiv) was then added. The mixture
was removed from the cooling bath and stirred for 6 h at room
temperature. The mixture was then quenched following the general
procedure. The crude was purified by flash column chromatography
(silica, pentane/Et2O 9/1), to afford the desired compound 8b as a
colorless liquid (331.5 mg, 70% yield). 1H NMR (400 MHz, CDCl3)
δ 6.16 (s, 1H), 5.60 (s, 1H), 4.17 (q, J ) 7.0 Hz, 2H), 2.69 (dd, J
) 14.4 Hz, J ) 9.3 Hz, 1H), 2.43 (m, 3H), 2.25 (m, 1H), 1.95 (m,
2H), 1.59 (m, 4H), 1.35 (m, 1H), 1.26 (t, J ) 7.1 Hz, 3H), 0.91 (t,
J ) 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 212.8, 167.1,
138.9, 126.4, 60.6, 54.5, 45.0, 41.2, 29.8, 28.4, 26.1, 25.2, 14.1,
10.7. IR (CDCl3) ν (cm-1) 3022, 2963, 1708, 1210. LRMS (EI, 70
eV, m/z) 238 M+•, 209 (M - Et)+•, 163 (base peak). HRMS m/z
M+• calcd for C14H22O3 238.1569, found 238.1557. [R]20D ) +15.1
(c 1.04, CHCl3). ee of 98.7% was estimated by two chiral GC:
one with a CHIRALSIL-DEX CB column (program: 90°-0′-1°/′-
170°-10′, speed 30 cm/s). For major dia tR: 58.78. For minor dia
tR: 5.95 and 10.362. The other with a CHIRAL-DEX G-TA column
(program: 100°-60′-1°/′-170°-5′, speed 47 cm/s). For major dia tR:
89.26 and 91.38 + for minor dia tR: 91.38.
C13H20O3 224.1412, found 224.1405. [R]20 ) +3.9 (c 1.17,
D
CHCl3). ee of 98.9% was measured by chiral GC with a CHIRAL-
SIL-DEX CB column (program: 90°-0′-1°/′-170°-10′, speed 30 cm/
s). tR: 51.29 and 51.68.
3-Methyl-2-[8-toluene-10-sulfonyl)allyl]-cyclohexanone (12c).
Following the general procedure ACA2 for the first step, the sulfone
3 (1.32 g, 4.8 mmol, 2.4 equiv) was then added. The mixture was
removed from the cooling bath and stirred for 6 h at room
temperature. The mixture was then quenched following the general
procedure. The product was purified by flash column chromatog-
raphy (silica, cyclohexane/ethyl acetate 8/2) to afford the desired
compound 12c as a colorless oil (446.9 mg, 73% yield). 1H NMR
(400 MHz, CDCl3) δ 7.74 (d, J ) 8.1 Hz, 2H), 7.33 (d, J ) 7.8
Hz, 2H), 6.35 (s, 1H), 5.81 (s, 1H), 2.68 (dd, J ) 15.4 Hz, J ) 9.4
Hz, 1H), 2.49 (dt, broad, J ) 9.1 Hz, J ) 1.0 Hz, 1H), 2.43 (s,
3H), 2.26 (m, 3H), 2.23 (dt, J ) 12.1 Hz, J ) 5.8 Hz, 1H), 2.00
(m, 1H), 1.83 (m, 1H), 1.56 (m, 2H), 1.46 (dt, J ) 12.5 Hz, J )
3.4 Hz, 1H), 1.03 (d, J ) 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 211.2, 148.6, 144.4, 135.9, 129.7, 128.2, 125.5, 55.9, 41.8, 39.9,
34.1, 26.33, 26.30, 21.6, 20.5. IR (CDCl3) ν (cm-1) 2956, 2923,
2863, 1704, 1597, 1457, 1429, 1399, 1383, 1309, 1298, 1286, 1163,
1155, 1133, 1078, 944, 916, 812, 727. LRMS (EI, 70 eV, m/z) 307
(M + H)+• 152 (M - SO2p-tol)+•, 151 (base peak), 91, 79. HRMS
m/z [M + H]+ calculated for C17H22O3S 307.1362, found 307.1375.
3-Ethyl-2-[8-toluene-10-sulfonyl)allyl]-cyclohexanone (8c). Fol-
lowing the general procedure ACA1 for the first step, the sulfone
3 (1.34 g, 4.8 mmol, 2.4 equiv) was then added. The mixture was
removed from the cooling bath and stirred for 7 h at room
temperature. The mixture was then quenched following the general
procedure. The product was purified by flash column chromatog-
raphy (silica, cyclohexane/ethyl acetate 8/2), to afford the desired
1
compound 8c as a colorless oil (383.8 mg, 60% yield). H NMR
(400 MHz, CDCl3) δ 7.73 (d, J ) 8.4 Hz, 2H), 7.33 (d, J ) 8.1
Hz, 2H), 6.34 (s, 1H), 5.77 (s, 1H), 2.64 (dd, J ) 15.7 Hz, J ) 9.1
Hz, 1H), 2.52 (dt, broad, J ) 9.1 Hz, J ) 2.3 Hz, 1H), 2.43 (s,
3H), 2.31 (m, 2H), 2.23 (dt, J ) 12.1 Hz, J ) 5.8 Hz, 1H), 2.00
(m, 1H), 1.88 (m, 1H), 1.54 (m, 2H), 1.41 (m, 2H), 1.27 (dt, J )
7.3 Hz, J ) 6.8 Hz, 1H), 0.87 (t, J ) 7.3 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 211.7, 148.6, 144.4, 135.9, 129.7, 128.2, 125.3,
53.6, 45.4, 41.6, 29.3, 26.6 (d, J ) 30.5 Hz), 26.1, 25.9, 21.6, 10.4.
IR (CDCl3) ν (cm-1) 2962, 2927, 2863, 1708, 1596, 1447, 1311,
1301, 1290, 1167, 1134, 1081, 951, 814, 731. LRMS (EI, 70 eV,
m/z) 321 (M + H)+•, 166 (M - SO2p-tol)+•, 165 (base peak) 123,
91. Elemental analysis for C18H24O3S: calcd C 66.50, H 7.53.
[R]20 ) -18.7 (c 0.99, CHCl3). ee of 99.1% was measured by
D
chiral SFC with a chiracel OB-H column (program: 3% MeOH-
7′-3-25%, 200 bar, 2 mL/min, 55 °C). For major dia tR: 4.45 and
5.53 + for minor dia tR: 5.99 and 10.362.
Found: C 67.47, H 7.55. [R]20 ) +29.3 (c 1.00, CHCl3). ee of
(3)-Ethyl-(2)-[(9-nitro)-allyl]-cycloheptanone (15a). Following
the general procedure ACA1 for the first step, the nitroolefin 1
(562.3 mg, 3 mmol, 1.5 equiv) was then added. The mixture was
removed from the cooling bath and stirred 6 h at room temperature.
The mixture was then quenched following the general procedure.
The product was purified by flash column chromatography (silica,
pentane/Et2O 8/2), to afford the desired compound 15a as a slightly
yellow liquid (305.6 mg, 68% yield). 1H NMR (400 MHz, CDCl3)
δ 6.43 (d, J ) 1.8 Hz, 1H), 5.61 (s, 1H), 2.88 (m, 2H), 2.67 (dt, J
) 8.1 Hz, J ) 3.3 Hz, 1H), 2.48 (m, 1H), 2.31 (td, J ) 13.5 Hz,
J ) 5.7 Hz, 1H), 1.77-1.58 (m, 5H), 1.52-1.39 (m, 3H), 1.31
(m, 1H), 0.95 (t, J ) 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
213.3, 155.8, 119.9, 54.8, 42.1, 41.8, 31.0, 29.7, 26.0, 25.1, 24.3,
11.3. IR (CDCl3) ν (cm-1) 2936, 2867, 1701, 1527, 1462, 1344,
1213, 1113 (broad), 949, 863. LRMS (EI, 70 eV, m/z) 180 (M -
NO2)+•, 179, 139, 121, 95, 79, 57, 55 (base peak). HRMS m/z [M
D
98.7% for major dia and ee of 99.1% for minor dia were measured
by chiral SFC with a CHIRALPAK AS column (program: 3%
MeOH-10′-1-25%, 200 bar, 2 mL/min, 30 °C). For major dia tR:
6.37 and 7.16. For minor dia tR: 7.97 and 11.61.
(3)-Methyl-(2)-[(8-nitro)-allyl]-cyclohexanone (12a). Following
the general procedure ACA2 for the first step, the nitroolefin 1
(562.5 mg, 3.0 mmol, 1.5 equiv) was then added. The mixture was
removed from the cooling bath and stirred for 3 h at room
temperature. The mixture was then quenched following the general
procedure. The product was purified by flash column chromatog-
raphy (silica, pentane/Et2O 8/2) to afford the desired compound
1
12a as a slightly yellow liquid (316.8 mg, 80% yield). H NMR
(400 MHz, CDCl3) δ 6.46 (s, 1H), 5.74 (s, 1H), 2.96 (dd, J ) 15.2
Hz, J ) 9.8 Hz, 1H), 2.77 (d, J ) 15.0 Hz, 1H), 2.33 (m, 1H),
2.06 (m, 1H), 1.89 (m, 1H), 1.67 (m, 2H), 1.52 (m, 1H), 1.18 (d,
J ) 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 211.1, 156.7,
+ H]+ calculated for C12H19O3N 226.1437, found 226.1463. [R]20
D
119.9, 55.6, 42.0, 40.1, 34.3, 27.1, 26.4, 20.5. IR (CDCl3) ν (cm-1
)
) -5.1 (c 1.02, CHCl3). ee of 91% was measured by chiral SFC
with a chiracel AD column (program: 2% MeOH-5′-1-10%, 200
bar, 2 mL/min, 30 °C). tR: 3.48 and 3.94.
2964, 2935, 1709, 1526, 1343. LRMS (EI, 70 eV, m/z) 152 (M -
NO2)+•, 109, 57 (base peak). HRMS m/z (M - H)+• calcd for
C10H14O3N 196.0974, found 196.0949, (M - NO2)+• calcd for
Ethyl 2-((2-Ethyl-7-oxocycloheptyl)methyl)acrylate (15b). Fol-
lowing the general procedure ACA1 for the first step, the bromoester
2 (928.0 mg, 4.8 mmol, 2.4 equiv) was then added. The mixture
was removed from the cooling bath and stirred for 6 h at room
temperature. The mixture was then quenched following the general
C10H15O 151.1123, found 151.1120. [R]20 ) +14.7 (c 1.00,
D
CHCl3). ee of 98.5% was measured by chiral SFC with a chiracel
AD column (program: 3% MeOH-5′-1-10%, 200 bar, 2 mL/min,
30 °C). tR: 2.95 and 3.47.
J. Org. Chem, Vol. 71, No. 15, 2006 5741

Rathgeb et al.
procedure. The product was purified by flash column chromatog-
raphy (silica, pentane/Et2O 8/2), to afford the desired compound
15b as a colorless liquid (361.7 mg, 72% yield). H NMR (400
by chiral GC with a chirasil-DEX CB column (program: 100°-0′-
1°/′-170°-10′, speed 31 cm/s), tR: 55.73 and 56.29.
1
MHz, CDCl3) δ 6.12 (d, J ) 1.3 Hz, 1H), 5.48 (d, J ) 1 Hz, 1H),
4.16 (m, 2H), 2.53 (m, 4H), 2.23 (m, 1H), 1.77 (m, 2H), 1.62 (m,
3H), 1.39 (m, 1H), 1.27 (t, J ) 7.2 Hz, 6H), 0.90 (t, J ) 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 214.6, 166.7, 138.3, 126.7,
60.6, 57.1, 41.9, 41.4, 33.4, 30.6, 26.9, 26.3, 25.6, 14.1, 11.2. IR
(CDCl3) ν (cm-1) 2931, 2863, 1706, 1630, 1446, 1410, 1369, 1297,
1192, 1175, 1156, 1116, 1026, 946, 818. LRMS (EI) m/z: 252 M+•,
223 (M - Et)+•, 177, 139, 126, 69, 55 (base peak). HRMS m/z [M
+ H]+ calculated for C15H24O3 253.1798, found 253.1781. Elemen-
tal analysis for C15H24O3: calcd C 71.39, H 9.59. Found: C 69.99,
Acknowledgment. We thank the Swiss National Science
Foundation (no. 200020-105368), and COST action D24/0003/
01 (OFES contract no. C02.0027) for financial support. Special
thanks, also, to Ste´phane Rosset for his help for the separation
of enantiomers on chiral GC or SFC.
Supporting Information Available: All NMR spectroscopic
data and chiral GC or SFC of described compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
H 9.24. [R]20 ) -15.3 (c 1.03, CHCl3). ee of 95% was measured
JO060814J
D
5742 J. Org. Chem., Vol. 71, No. 15, 2006