Construction of quaternary stereocenters by nickel-catalysis of asymmetric Michael reactions

Article abstract of DOI:10.1002/(SICI)1099-0690(200003)2000:5<701::AID-EJOC701>3.0.CO;2-5

Quaternary stereocenters were constructed with an enantio-selectivity of up to 91‰ ee under aerobic conditions and at ambient temperature in the Michael reaction of β-dicarbonyl compounds and methyl vinyl ketone with Ni(OAc)₂·4H₂O an

Full text of DOI:10.1002/(SICI)1099-0690(200003)2000:5<701::AID-EJOC701>3.0.CO;2-5

SHORT COMMUNICATION
Construction of Quaternary Stereocenters by Nickel-Catalysis of Asymmetric
Michael Reactions
Jens Christoffers,*[a] Ulrich Rößler,[a] and Thomas Werner[a]
Keywords: Asymmetric catalysis / Catalysis / Michael additions / N ligands / Nickel
Quaternary stereocenters were constructed with an enantio-
selectivity of up to 91% ee under aerobic conditions and at
ambient temperature in the Michael reaction of β-dicarbonyl
compounds and methyl vinyl ketone with Ni(OAc)2 4H2O
and optically active trans-1,2-diaminocyclohexane as
a
chiral catalyst.
Introduction
Results and Discussion
In the course of our search for a chiral catalyst we have
found a combination of metal salt and chiral ligand which
catalyzes the conversion of Michael donor 1a with methyl
vinyl ketone (MVK, 2) to give the product 4a with 91% ee
(Scheme 1). In a typical procedure one equiv. of 1a and 1.2
equiv. of 2 in CHCl3 under aerobic conditions and at ambi-
ent temperature give the product 4a with the above men-
tioned selectivity and in 37% yield using a catalyst gener-
ated in situ from 0.05 equiv. Ni(OAc)2 4H2O and 0.375
equiv. (R,R)-trans-1,2-diaminocyclohexane (3) (Scheme 1).
A higher selectivity in the synthesis of 4a (93% ee) has been
achieved so far only at –50 °C by use of the La-Na-BINOL
complex (LSB) according to Shibasaki et al.[9] Koga and
co-workers achieved 90% ee at –100 °C by the use of a
chiral auxiliary and a stoichiometric amount of a base.[10]
Consequently, we report herein on the first enantioselective
preparation of 4a exceeding 90% ee at room temperature
and without anhydrous conditions.
The Michael reaction is one of the most important C–C
bond forming reactions and is usually catalyzed by a strong
Brönstedt base.[1] However, under basic reaction conditions
the chemoselectivity of this method suffers from a number
of drawbacks, namely side reactions and subsequent pro-
cesses such as aldol-cyclizations and retro-Claisen type de-
compositions. These disadvantages can be avoided by the
use of transition metal catalysts which, moreover, allow an
asymmetric catalysis of this reaction by the application of
chiral ligands.[2,3]
Shibasaki et al. recently introduced the excellent hetero-
bimetallic LSB-catalyst for the Michael reaction of 1,3-di-
carbonyl compounds with α,β-unsaturated ketones. How-
ever, the reaction conditions are strongly basic and there-
fore often lead to the above-mentioned disadvantages.[4]
The use of a neutral transition metal catalyst has been in-
vestigated with varying degrees of success by a number of
groups in the past few years: Brunner et al. introduced Co-
(acac)2 together with an optically active diamine,[5] Desi-
moni et al. reported on chiral copper catalysts derived from
natural α-amino acids,[6] and Pfaltz et al. presented chiral
tetradentate oxazolines as ligands for CoII-catalyzed asym-
metric Michael reactions.[7] All these methods, however, suf-
fer either from the need for anhydrous reaction conditions,
low reaction temperatures or low yields.
We are searching for an alternative to ShibasakiЈs bime-
tallic catalysis of the Michael reaction,[4] which avoids basic
reaction conditions, and we have already reported on this
subject several times.[8] It is our strategy to screen a large
number of metal complexes, generated in situ by the com-
bination of many ligands with metal salts, for their activity
and selectivity. Herein we wish to report on a new NiII-
catalyzed asymmetric Michael reaction under aerobic reac-
tion conditions as an alternative to, and in completion of,
the existing procedures.
Scheme 1
Our methodology is a case of ligand-accelerated catalysis,
since the nickel salt or ligand 3 alone show no catalytic
activity (after three days the conversion is less than 10%).
Regarding the donor, 0.05 equiv. Ni salt were applied. The
selectivity was strongly dependent on the ligand-to-Ni ratio
and was found to be optimal at 7.5:1 with 91% ee. Different
ligand-to-Ni ratios gave lower selectivities (e.g. 82% ee at
1:1, and 70% ee at 20:1). The use of other solvents (CH2Cl2:
88% ee, MeOtBu: 81% ee) or the variation of the temper-
ature (0 °C: 88% ee, 40 °C: 89% ee) gave no further im-
provement. Below 0 °C the turnover rate was very low. The
reaction tolerates air and moisture (addition of water does
not lower the selectivity); however, an excess of the acceptor
had to be added in order to minimize formation of the by-
[a]
Technische Universität Berlin, Institut für Organische Chemie,
Sekretariat C 3,
Straße des 17. Juni 135, D-10623 Berlin, Germany,
Fax: (internat.) ϩ 49-30/723-1233,
E-mail: jchr@wap0105.chem.tu-berlin.de
Eur. J. Org. Chem. 2000, 701Ϫ705
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0305Ϫ0701 $ 17.50ϩ.50/0
701

J. Christoffers, U. Rößler, T. Werner
SHORT COMMUNICATION
product 5[11] (Scheme 2). Both enantiomers of the diamine sion into compound 6a.[14] In case of 4e and 4f, selectivities
3 can be obtained in large quantities by simple resolution were determined after transesterification with DMAP (4c
of the racemate with tartaric acid.[12] Ligand 3 (0.375 equiv. from 4e, 4b from 4f); the configurations of compounds 4b–
based on 1a) does not, however, act catalytically, but as an f were correlated by pairs. The selectivities of compounds
auxiliary. Initial results show that 3 can be partly recovered 4d, 4g and 4i were determined after derivatization to the
after workup.
corresponding bicyclic aldol products with conc. H2SO4:
7[15] from 4d, 6b[16] from 4g, and 8 from 4i[17] (Scheme 2).
With regard to the mechanism of the overall conversion,
we can only speculate at the moment. We were, however,
able to show that the primary diamine 3 reacts rapidly with
donor 1a in the presence of a catalytic amount of nickel
acetate to form an enamine,[18] which could coordinate to a
nickel center as a tridentate ligand as shown in structure 9
(Scheme 2). By this coordination of the derived donor to
the nickel atom the planar dionato system is subject to dia-
stereofacial differentiation. Moreover, the acceptor 2 is ac-
tivated by coordination to the Lewis acidic metal center. A
detailed experimental study of a model intermediate 9 is the
subject of present work in our laboratory. Moreover, we are
making great efforts to improve the so far moderate yields,
to minimize the amount of optically active diamine and to
improve the enantioselectivities of the donors 1b to 1i.
Scheme 2
We tried to transfer the result obtained for 1a to other
Michael donor molecules. The selectivities obtained in the
conversion of cyclic β-keto esters and β-diketones 1b to 1i
are lower (Table 1), but in case of the iso-butyl ester 4e (74%
ee) still significant. However, it is remarkable that the use
of a different alcohol residue at the cyclic keto esters may
invert the selectivity: compound 4e was obtained as the (S)-
enantiomer, while all other five-membered ring products
yielded the (R)-compound as the major isomer.
Conclusion
Quaternary stereocenters can be constructed enantiose-
lectively by Michael reactions of cyclic β-dicarbonyl com-
pounds with methyl vinyl ketone. The chiral catalyst is gen-
erated in situ by combination of Ni(OAc)2 4H2O with
optically active trans-1,2-diaminocyclohexane. In at least
one case the selectivity exceeds 90% ee. Importantly, this
result was obtained at ambient temperature under neutral
reaction conditions and without exclusion of air and mois-
ture, which is a significant improvement on current proced-
ures. However, the isolated yield of the product did not ex-
ceed the amount of applied chiral diamine.
Table 1. Asymmetric NiII-catalyzed Michael reaction with trans-
1,2-diaminocyclohexane as auxiliary
Experimental Section
General: Column chromatography was accomplished with Merck
silica gel (Type 60, 0.063–0.200 mm) using tert-butyl methyl ether
1
(MTB) and hexanes (PE) as solvents. – H NMR spectra were re-
corded with Bruker AM 400 (400 MHz) and Bruker AC 200
(200 MHz). – 13C NMR spectra were recorded with a Bruker AC
200 (50 MHz), assignments were made using DEPT experiments. –
MS spectra were obtained with a Varian MAT 711 and MAT 955Q
(high resolution). – IR spectra were recorded with a Nicolet Magna
IR 750. – Elemental analyses were obtained with an Analytik Jena
Vario EL. – Optical rotations were measured with a Perkin–Elmer
polarimeter 341. – Chiral GC analysis was performed with a Pack-
ard 437A with FI detection, a Shimadzu C-R6A integrator and a
Macherey–Nagel column FS-LIPODEX E (25 m, 0.25 mm) with
nitrogen carrier gas.
[a] Use of (R,R)-3. – [b] Use of (S,S)-3 yields (S)-(–)-4a with 91% ee.
Details of the preparation of 4b to 4i are contained in
the Experimental Section. Selectivities have been analyzed
by chiral GC and configurations have been assigned by
comparison with literature values.[13] In the case of 4a the
Starting materials 1a, 1b, 1c, 1g and 2a were commercially available
and used as purchased. Compounds 1e[19] and 3 (both enanti-
omers)[12] were prepared according to literature protocols. The syn-
exact enantiomeric ratio was double checked after conver- thesis of racemates of 4a, 4c, 4e, 4g, and 4h[20] and of by-product
702
Eur. J. Org. Chem. 2000, 701Ϫ705

Nickel-Catalysis of Asymmetric Michael Reactions
SHORT COMMUNICATION
5[11] as well as their analytical and spectroscopic data have been
reported previously.
reacted without additional solvent to yield the title compound 4d
(563 mg, 2.34 mmol, 71%) after removal of all volatile materials in
vacuo and Kugelrohr distillation of the residue (oven temp. 150 °C,
p ϭ 0.1 mm) as a colorless oil. – 1H NMR (200 MHz, CDCl3): δ ϭ
1.19 (d, J ϭ 6.3 Hz, 3 H), 1.21 (d, J ϭ 6.2 Hz, 3 H), 1.77–2.16 (m,
4 H), 2.10 (s, 3 H), 2.19–2.51 (m, 5 H), 2.70 (ddd, J ϭ 17.7 Hz,
J ϭ 9.6 Hz, J ϭ 5.8 Hz, 1 H), 4.98 (heptet, J ϭ 6.3 Hz, 1 H). –
13C{1H} NMR (50 MHz, CDCl3): δ ϭ 19.5 (CH2), 21.5 (CH3),
21.6 (CH3), 26.9 (CH2), 29.9 (CH3), 34.4 (CH2), 37.9 (CH2), 38.8
(CH2), 58.9 (C), 68.9 (CH), 170.9 (C), 207.9 (C), 214.9 (C). – MS
(EI, 70 eV); m/z (%): 240 (8) [Mϩ], 212 (42), 170 (74), 152 (38), 137
(77), 128 (72), 125 (100). – IR (ATR): ν˜ ϭ 1748 (s), 1717 (vs), 1168
(s), 1105 (s) cm–1. – C13H20O4 (240.3): calcd. C 64.98, H 8.39; found
C 64.84, H 8.58. – HRMS: calcd. 240.1362; found 240.1362.
Isopropyl 2-Oxocyclopentanecarboxylate (1d): Oxo ester 1c (10.9 g,
69.8 mmol) and DMAP (426 mg, 3.49 mmol) were dissolved in
iPrOH (39.6 g, 659 mmol) and heated to reflux for 12 h. All volatile
materials were removed in vacuo and the residue redissolved in
iPrOH (42.1 g, 701 mmol). The mixture was heated to reflux again
for 15 h, then all volatile materials were removed in vacuo and the
residue fractionated in high vacuum through a 10 cm Vigreux col-
umn to yield the title compound 1d as a colorless liquid (9.71 g,
57.0 mmol, 81%), bp. 53 °C/0.1 mm. – 1H NMR (200 MHz,
CDCl3): δ ϭ 1.22 (d, J ϭ 6.3 Hz, 3 H), 1.24 (d, J ϭ 6.3 Hz, 3 H),
1.71–1.94 (m, 1 H), 2.01–2.17 (m, 1 H), 2.19–2.36 (m, 4 H), 3.08
(t, J ϭ 8.9 Hz, 1 H), 5.02 (heptet, J ϭ 6.3 Hz, 1 H). – 13C{1H}
NMR (50 MHz, CDCl3): δ ϭ 20.6 (CH2), 21.3 (CH3), 21.4 (CH3),
27.0 (CH2), 37.7 (CH2), 54.6 (CH), 68.4 (CH), 168.7 (C), 212.1
(C). – MS (EI, 70 eV); m/z (%): 170 (21) [Mϩ], 142 (20), 111 (100),
100 (74), 73 (44), 55 (46). – IR (ATR): ν˜ ϭ 2980 (s), 1754 (vs), 1721
(vs), 1374 (s), 1297 (s), 1256 (s), 1193 (s), 1146 (s), 1105 (vs)
cm–1. – C9H14O3 (170.2): calcd. C 63.51, H 8.29; found C 62.78, H
8.06. – HRMS: calcd. 170.0943; found 170.0945.
rac-Benzyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (4f): Fol-
lowing GP1, oxo ester 1f (546 mg, 2.50 mmol), MVK (2) (210 mg,
3.00 mmol) and FeCl3 6H2O (33.8 mg, 0.13 mmol) in CH2Cl2
(0.5 mL) were reacted to yield the title compound 4f after chroma-
tography (SiO2, PE/MTB 1:1, Rf ϭ 0.23) as a colorless oil (643 mg,
2.23 mmol, 89%). – 1H NMR (400 MHz, CDCl3): δ ϭ 1.84–2.04
(m, 4 H), 2.07 (s, 3 H), 2.09–2.18 (m, 1 H), 2.22–2.50 (m, 4 H),
2.64 (ddd, J ϭ 17.9 Hz, J ϭ 9.7 Hz, J ϭ 5.7 Hz, 1 H), 5.12 (d, J ϭ
12.4 Hz, 1 H), 5.16 (d, J ϭ 12.4 Hz, 1 H), 7.26–7.38 (m, 5 H). –
13C{1H} NMR (50 MHz, CDCl3): δ ϭ 19.1 (CH2), 26.6 (CH2),
29.3 (CH3), 33.6 (CH2), 37.4 (CH2), 38.2 (CH2), 58.4 (C), 66.4
(CH2), 127.4 (2 CH), 127.8 (CH), 128.1 (2 CH), 135.1 (C), 170.6
(C), 207.0 (C), 213.9 (C). – MS (EI, 70 eV); m/z (%): 288 (1) [Mϩ],
179 (28), 169 (77), 154 (28), 91 (100), 65 (29). – IR (ATR): ν˜ ϭ
1748 (s), 1716 (vs), 1162 (s) cm–1. – C17H20O4 (288.3): calcd. C
70.81, H 6.99; found C 70.73, H 7.01. – HRMS: calcd. 288.1362;
found 288.1365.
Benzyl 2-Oxocyclopentanecarboxylate (1f): Oxo ester 1b (9.93 g,
69.8 mmol), benzyl alcohol (8.31 g, 76.8 mmol), DMAP (427 mg,
3.50 mmol), and cyclohexane (50 mL) were heated to reflux in a
Dean–Stark trap for 20 h. The solvent was removed by rotary evap-
oration and the residue vacuum distilled through a 10 cm Vigreux
column (bp. 150 °C/0.1 mm) to yield the title compound 1f (13.5 g,
61.9 mmol, 89%) as a colorless oil. – 1H NMR (200 MHz, CDCl3):
δ ϭ 1.71–1.88 (m, 1 H), 2.03–2.22 (m, 1 H), 2.25–2.57 (m, 4 H),
3.21 (t, J ϭ 9.1 Hz, 1 H), 5.18 (s, 2 H), 7.33–7.38 (m, 5 H). –
13C{1H} NMR (50 MHz, CDCl3): δ ϭ 20.7 (CH2), 27.2 (CH2),
37.9 (CH2), 54.6 (CH), 66.8 (CH2), 127.9 (CH), 128.1 (CH), 128.4
(CH), 135.5 (C), 169.1 (C), 211.9 (C). – MS (EI, 70 eV); m/z (%):
218 (23) [Mϩ], 190 (59), 91 (100), 84 (88), 65 (44). – IR (ATR): ν˜ ϭ
1753 (vs), 1723 (vs), 1295 (s), 1253 (s), 1182 (s), 1157 (s), 1109 (s),
749 (s), 698 (s) cm–1. – C13H14O3 (218.3): calcd. C 71.50, H 6.47;
found C 71.51, H 6.46. – HRMS: calcd. 218.0943; found 218.0945.
rac-2-Acetyl-2-(3-oxobutyl)cyclohexanone (4i): Following GP1, di-
ketone 1i (350 mg, 2.50 mmol), MVK (2) (210 mg, 3.00 mmol) and
FeCl3 6H2O (33.8 mg, 0.13 mmol) in CH2Cl2 (0.5 mL) were re-
acted to yield the title compound 4i after chromatography (SiO2,
PE/MTB 1:1, Rf ϭ 0.17) as a colorless oil (413 mg, 1.96 mmol,
79%). – 1H NMR (400 MHz, CDCl3): δ ϭ 1.46–2.08 (m, 7 H), 2.10
(s, 3 H), 2.12 (s, 3 H), 2.26–2.50 (m, 5 H). – 13C{1H} NMR
(50 MHz, CDCl3): δ ϭ 21.9 (CH2), 26.0 (CH3), 26.9 (CH2), 27.0
(CH2), 29.8 (CH3), 34.7 (CH2), 38.1 (CH2), 41.1 (CH2), 66.4 (C),
207.5 (C), 207.6 (C), 209.9 (C). – MS (EI, 70 eV); m/z (%): 210 (2)
[Mϩ], 168 (53), 150 (32), 111 (100), 98 (41). – IR (ATR): ν˜ ϭ 1713
(vs), 1694 (vs), 1358 (s), 1165 (s) cm–1. – C12H18O3 (210.3): calcd.
C 68.55, H 8.63; found C 68.02, H 8.63. – HRMS: calcd. 210.1256;
found 210.1255.
General Procedure 1 (GP1). – Iron(III)-Catalyzed Synthesis of
Racemates: A mixture of donor 1 (1.00 equiv.), MVK (2) (1.20
equiv.) and FeCl3 6H2O (0.0500 equiv.) in CH2Cl2 (0.1 mL/mmol
donor 1) or without solvent was stirred at ambient temperature for
ca. 18 h. The mixture was directly chromatographed on SiO2 (PE/
MTB 1:1) to yield the Michael reaction product 4 in 75–95% yield.
rac-Methyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (4b): Fol-
lowing GP1, oxo ester 1b (485 mg, 3.41 mmol), MVK (2) (359 mg,
5.12 mmol) and FeCl3 6H2O (46.1 mg, 0.17 mmol) were reacted
without additional solvent to yield the title compound 4b after
chromatography (SiO2, PE/MTB 1:1, Rf ϭ 0.26) as a colorless oil
(651 mg, 3.07 mmol, 90%). – 1H NMR (200 MHz, CDCl3): δ ϭ
1.75–2.12 (m, 5 H), 2.07 (s, 3 H), 2.23–2.48 (m, 4 H), 2.61 (ddd,
J ϭ 17.9 Hz, J ϭ 9.4 Hz, J ϭ 6.0 Hz, 1 H), 3.64 (s, 3 H). – 13C{1H}
NMR (50 MHz, CDCl3): δ ϭ 19.4 (CH2), 26.6 (CH2), 29.8 (CH3),
34.1 (CH2), 37.8 (CH2), 38.7 (CH2), 52.4 (CH3), 58.8 (C), 171.7
(C), 207.6 (C), 214.6 (C). – MS (EI, 70 eV); m/z (%): 212 (6) [Mϩ],
184 (100), 142 (39), 137 (43), 125 (76), 111 (47), 110 (56), 97 (49). –
IR (ATR): ν˜ ϭ 1748 (s), 1715 (vs), 1165 (s), 1117 (m) cm–1. –
C11H16O4 (212.3): calcd. C 62.25, H 7.60; found C 62.19, H 7.78. –
HRMS: calcd. 212.1049; found 212.1044.
General Procedure 2 (GP2). – Asymmetric Nickel(II) Catalysis:
Ni(OAc)2 4H2O (0.05 equiv.) was added to a solution of (R,R)-3
(0.375 equiv.) in CHCl3 (1.0 mL/mmol donor 1) and the mixture
was stirred for 1 h at 23 °C. Donor 1 (1.00 equiv.), and after further
stirring for 2 h at 23 °C, MVK 2 (1.20 equiv.) were added. After
stirring for 16 h at 23 °C all volatile materials were removed in
vacuo and the residue was chromatographed on SiO2 (PE/MTB
1:1).
(R)-(؉)-Ethyl 2-Oxo-1-(3-oxobutyl)cyclohexanecarboxylate (R-4a):
According to GP2, donor 1a (1.97 g, 11.6 mmol), acceptor 2
(974 mg, 13.9 mmol), diamine (R,R)-3 (496 mg, 4.34 mmol) and
Ni(OAc)2 4H2O (144 mg, 0.58 mmol) were reacted. After chroma-
tography on SiO2 (PE/MTB 1:1), donor 1a was partly recovered in
a first fraction (528 mg, 3.10 mmol, 27%, Rf ϭ 0.55). Fraction 2
rac-Isopropyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (4d):
Following GP1, oxo ester 1d (560 mg, 3.29 mmol), MVK (2) contained product (R)-4a (colorless oil, 1.04 g, 4.33 mmol, 37% reg.
(349 mg, 4.94 mmol) and FeCl3 6H2O (44 mg, 0.17 mmol) were
1a, 100% based on 3, Rf ϭ 0.27). Finally, a third fraction was eluted
Eur. J. Org. Chem. 2000, 701Ϫ705
703

J. Christoffers, U. Rößler, T. Werner
SHORT COMMUNICATION
containing compound 5 (colorless oil, 201 mg, 1.09 mmol, 9% reg. termined after conversion into compound 6b according to GP3.
1a, Rf ϭ 0.21).
Optical rotation of a 2% ee material: [α]2D3 ϭ –2.3 (c ϭ 7.1, CHCl3).
Compound 4a was analyzed by chiral GC: isotherm elution at 115
°C, t(S) ϭ 114.2 min, t(R) ϭ 120.8 min. Enantiomeric excess was
checked after conversion into compound 6a according to GP3. Op-
(–)-2-Acetyl-2-(3-oxobutyl)cyclopentanone (4h): According to GP2,
donor 1h (407 mg, 3.23 mmol), acceptor 2 (271 mg, 3.87 mmol),
diamine (R,R)-3 (138 mg, 1.21 mmol) and Ni(OAc)2 4H2O
(40.1 mg, 0.16 mmol) were reacted to yield compound 4h (263 mg,
1.34 mmol, 41%) after chromatography on SiO2 (PE/MTB 1:1,
Rf ϭ 0.12). Chiral GC: isotherm elution at 115 °C: t1 ϭ 90.5 min,
t2 ϭ 100.2 min. Optical rotation of a 7% ee material: [α]2D3 ϭ –10.6
(c ϭ 4.1, CHCl3).
tical rotation of a 91% ee material: [α]2D3 ϭ ϩ88.5 (c ϭ 3.3, CHCl3),
23
[α] ϭ ϩ93.3 (c ϭ 6.9, CCl4).
578
Use of diamine (S,S)-3 yielded product (S)-4a (89.1 mg, 0.37 mmol,
37%) from 1a (170 mg, 1.00 mmol) with 91% ee. – [α]2D3 ϭ –87.9
23
(c ϭ 3.4, CHCl3), [α] ϭ –91.3 (c ϭ 6.9, CCl4).
578
(؉)-2-Acetyl-2-(3-oxobutyl)cyclohexanone (4i): According to GP2,
donor 1i (140 mg, 1.00 mmol), acceptor 2 (84.1 mg, 1.20 mmol),
diamine (R,R)-3 (42.8 mg, 0.375 mmol) and Ni(OAc)2 4H2O
(12.4 mg, 0.050 mmol) were reacted to yield compound 4i (120 mg,
0.57 mmol, 57%) after chromatography on SiO2 (PE/MTB 1:1,
Rf ϭ 0.17). Enantiomeric excess was determined after conversion
(R)-(–)-Methyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (R-
4b): According to GP2, donor 1b (574 mg, 4.04 mmol), acceptor
2 (340 mg, 4.85 mmol), diamine (R,R)-3 (214 mg, 1.87 mmol) and
Ni(OAc)2 4H2O (50.3 mg, 0.202 mmol) were reacted to yield com-
pound (R)-4b (305 mg, 1.44 mmol, 36%) after chromatography on
SiO2 (PE/MTB 1:1, Rf ϭ 0.16). Chiral GC: isotherm elution at 115
°C: t(S) ϭ 78.1 min, t(R) ϭ 81.2 min. Optical rotation of a 31% ee
material: [α]2D3 ϭ –5.6 (c ϭ 9.9, CHCl3).
into compound 8 according to GP3. Optical rotation of a 41% ee
23
material: [α]2D3 ϭ ϩ66.4 (c 12.2, CHCl3), [α]
ϭ ϩ63.8 (c ϭ
578
15.6, C6H6).
(R)-(–)-Ethyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (R-4c):
According to GP2, donor 1c (125 mg, 0.80 mmol), acceptor 2
(67.9 mg, 1.00 mmol), diamine (R,R)-3 (35.1 mg, 0.31 mmol) and
Ni(OAc)2 4H2O (10.0 mg, 0.040 mmol) were reacted to yield com-
pound (R)-4c (73.0 mg, 0.32 mmol, 40%) after chromatography on
SiO2 (PE/MTB 1:1, Rf ϭ 0.25). Chiral GC: isotherm elution at 130
°C: t(S) ϭ 32.9 min, t(R) ϭ 34.7 min. Optical rotation of a 40% ee
material: [α]2D3 ϭ –6.9 (c ϭ 5.3, CHCl3).
General Procedure 3 (GP3). – Derivatization of Compounds 4 with
conc. H2SO4: Compound 4 was dissolved in a threefold volume of
conc. H2SO4 and stirred for ca. 18 h at ambient temperature (at 50
°C for compound 4a). Ice was added to the mixture, and the re-
sulting aqueous solution was extracted with MTB. After washing
with NaHCO3 (saturated aqueous solution) and drying (Na2SO4)
the organic extract was evaporated and the residue chromato-
graphed on SiO2 (PE/MTB 1:1).
(R)-(؉)-Isopropyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (R-
4d): According to GP2, donor 1d (137 mg, 0.81 mmol), acceptor 2
(67.8 mg, 0.967 mmol), diamine (R,R)-3 (34.6 mg, 0.30 mmol) and
Ni(OAc)2 4H2O (10.1 mg, 0.041 mmol) were reacted to yield com-
pound (R)-4d (102 mg, 0.42 mmol, 53%) after chromatography on
SiO2 (PE/MTB 1:1, Rf ϭ 0.24). Enantiomeric excess of (R)-4d was
determined after conversion into compound 7 according to GP3.
Optical rotation of a 6% ee material: [α]2D3 ϭ ϩ0.2 (c ϭ 11.4,
CHCl3).
Ethyl Bicyclo[4.4.0]dec-1-en-3-one-6-carboxylate (6a): According to
GP3, compound 4a (250 mg, 1.04 mmol) was converted into 6a
(colorless oil, 103 mg, 0.46 mmol, 45%, Rf ϭ 0.31). Chiral GC:
gradient elution from 115 °C to 160 °C with 0.5 K min–1, t(S) ϭ
58.9 min, t(R) ϭ 62.7 min. – 1H NMR (200 MHz, CDCl3): δ ϭ
1.25 (t, J ϭ 7.2 Hz, 3 H), 1.30–1.47 (m, 2 H), 1.68–1.98 (m, 3 H),
1.24–2.46 (m, 7 H), 4.20 (q, J ϭ 7.1 Hz, 2 H), 5.91 (s, 1 H). –
13C{1H} NMR (50 MHz, CDCl3): δ ϭ 14.2 (CH3), 23.2 (CH2),
26.5 (CH2), 34.2 (CH2), 34.7 (CH2), 34.8 (CH2), 38.4 (CH2), 48.9
(C), 61.4 (CH2), 126.5 (CH), 163.1 (C), 173.4 (C), 198.9 (C). – MS
(EI, 70 eV); m/z (%): 222 (54) [Mϩ], 149 (100), 138 (24), 122 (52),
107 (50), 91 (46), 79 (44). – IR (ATR): ν˜ ϭ 2936 (s), 1724 (vs),
1679 (vs), 1258 (s), 1233 (s), 1231 (s), 1185 (s) cm–1. – C13H18O3
(222.3): calcd. C 65.53, H 7.61; found C 65.91, H 7.79. – HRMS:
calcd. 222.1256; found 222.1255.
(S)-(–)-Isobutyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (S-
4e): According to GP2, donor 1e (297 mg, 1.61 mmol), acceptor 2
(136 mg, 1.94 mmol), diamine (R,R)-3 (85.6 mg, 0.749 mmol) and
Ni(OAc)2 4H2O (20.1 mg, 0.081 mmol) were reacted to yield com-
pound (S)-4e (126 mg, 0.50 mmol, 31%) after chromatography on
SiO2 (PE/MTB 1:1, Rf ϭ 0.24). The enantiomeric excess of (S)-4e
was determined after transesterification to (S)-4c according to
GP4. Optical rotation of a 74% ee material: [α]2D3 ϭ –2.1 (c ϭ 6.1,
CHCl3).
Methyl Bicyclo[5.4.0]undec-7-en-9-one-1-carboxylate (6b): Accord-
ing to GP3, compound 4g (985 mg, 4.10 mmol) was converted into
6b (colorless oil, 351 mg, 1.58 mmol, 39%, Rf ϭ 0.29). Chiral GC:
gradient elution from 115 °C to 160 °C with 0.33 K min–1, t1
ϭ
(R)-(–)-Benzyl 2-Oxo-1-(3-oxobutyl)cyclopentanecarboxylate (R-4f):
According to GP2, donor 1f (218 mg, 1.00 mmol), acceptor 2
(84.1 mg, 1.20 mmol), diamine (R,R)-3 (42.8 mg, 0.375 mmol) and
Ni(OAc)2 4H2O (12.4 mg, 0.050 mmol) were reacted to yield com-
pound (R)-4f (225 mg, 0.78 mmol, 78%) after chromatography on
SiO2 (PE/MTB 1:1, Rf ϭ 0.23). The enantiomeric excess of (R)-4f
was determined after transesterification to (R)-4b according to
GP4. Optical rotation of a 21% ee material: [α]2D3 ϭ –0.5 (c ϭ
44.1, CHCl3).
94.5 min, t2 ϭ 98.0 min. – 1H NMR (400 MHz, CDCl3): δ ϭ 1.19–
1.38 (m, 2 H), 1.43–1.55 (m, 1 H), 1.61–1.83 (m, 3 H), 1.86–1.95
(m, 1 H), 1.97–2.11 (m, 2 H), 2.25 (dt, J ϭ 13.4 Hz, J ϭ 3.9 Hz, 1
H), 2.30–2.44 (m, 2 H), 2.45–2.52 (m, 2 H), 3.69 (s, 3 H), 5.96 (s,
1 H). – 13C{1H} NMR (50 MHz, CDCl3): δ ϭ 23.8 (CH2), 30.2
(CH2), 30.7 (CH2), 33.2 (CH2), 34.8 (CH2), 35.7 (CH2), 37.1 (CH2),
51.0 (C), 52.4 (CH3), 129.5 (CH), 167.0 (C), 174.5 (C), 198.8 (C). –
MS (EI, 70 eV); m/z (%): 222 (60) [Mϩ], 166 (46), 163 (100), 121
(38). – IR (ATR): ν˜ ϭ 2928 (s), 1726 (vs), 1680 (vs), 1447 (s), 1248
(s), 1210 (s), 1163 (s) cm–1. – HRMS: calcd. 222.1256; found
222.1252.
(–)-Methyl 2-Oxo-1-(3-oxobutyl)cycloheptanecarboxylate (4g): Ac-
cording to GP2, donor 1g (137 mg, 0.81 mmol), acceptor 2
(67.8 mg, 0.97 mmol), diamine (R,R)-3 (34.7 mg, 0.304 mmol) and
Ni(OAc)2 4H2O (10.1 mg, 0.041 mmol) were reacted to yield com-
pound 4g (27.0 mg, 0.11 mmol, 14%) after chromatography on
SiO2 (PE/MTB 1:1, Rf ϭ 0.18). Enantiomeric excess of 4g was de-
Isopropyl 5-Methyl-6-oxabicyclo[3.2.2]nonan-7-one-1-carboxylate
(7): According to GP3, compound 4d (132 mg, 0.55 mmol) was
converted into 7 (colorless oil, 29 mg, 0.12 mmol, 22%, Rf ϭ 0.30).
704
Eur. J. Org. Chem. 2000, 701Ϫ705

Nickel-Catalysis of Asymmetric Michael Reactions
SHORT COMMUNICATION
in Topics in Stereochemistry (Eds.: E. L. Eliel, S. H. Wilen),
Wiley Interscience, New York, 1989, vol. 19, p. 227–407. – [1c] P.
Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Tetrahedron Organic Chemistry Series vol. 9, Pergamon, Ox-
ford, 1992.
Chiral GC: isotherm elution at 115 °C, t1 ϭ 233 min, t2
ϭ
1
241 min. – H NMR (400 MHz, CDCl3): δ ϭ 1.27 (d, J ϭ 6.2 Hz,
6 H), 1.40 (s, 3 H), 1.76–1.89 (m, 4 H), 1.94–2.00 (m, 2 H), 2.20
(dd, J ϭ 10.9 Hz, J ϭ 5.8 Hz, 1 H), 2.08–2.13 (m, 1 H), 2.55–2.62
(m, 1 H), 5.08 (heptet, J ϭ 6.3 Hz, 1 H). – 13C{1H} NMR
(50 MHz, CDCl3): δ ϭ 20.7 (CH2), 21.5 (CH3), 21.7 (CH3), 24.6
(CH2), 29.6 (CH2), 30.1 (CH3), 30.9 (CH2), 38.1 (CH2), 51.8 (C),
69.2 (CH), 82.8 (C), 170.9 (C), 173.0 (C). – MS (EI, 70 eV); m/z
(%): 240 (4) [Mϩ], 212 (36), 170 (65), 137 (82), 125 (100), 111 (69),
97 (78). – IR (ATR): ν˜ ϭ 2979 (s), 1739 (vs), 1722 (vs), 1374 (s),
1263 (s), 1232 (s), 1192 (s), 1158 (s), 1106 (s), 1047 (s) cm–1. –
C13H20O4 (240.3): calcd. C 64.98, H 8.39; found C 64.32, H 8.32. –
HRMS: calcd. 240.1361; found 240.1364.
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J. H. Nelson, P. N. Howells, G. C. DeLullo, G. L. Landen,
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[3a]
Reviews:
J. Christoffers, Eur. J. Org. Chem. 1998, 1259–
[3b]
1266. –
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4-Methylspiro[5.5]undec-3-en-2,7-dione (8): According to GP3,
compound 4i (187 mg, 0.89 mmol) was converted into 8 (colorless
solid, 22.0 mg, 0.11 mmol, 13%, Rf ϭ 0.18). Chiral GC: gradient
elution from 100 °C to 140 °C with 0.25 K min–1, t1 ϭ 97.5 min,
t2 ϭ 115.1 min. – 1H NMR (400 MHz, CDCl3): δ ϭ 1.52 (ddd, J ϭ
13.8 Hz, J ϭ 10.2 Hz, J ϭ 3.6 Hz, 1 H), 1.66–1.80 (m, 3 H), 1.80–
1.90 (m, 1 H), 1.93 (s, 3 H), 1.96–2.04 (m, 1 H), 2.22–2.44 (m, 3
H), 2.44–2.58 (m, 2 H), 2.75 (ddd, J ϭ 14.2 Hz, J ϭ 10.2 Hz, J ϭ
5.8 Hz, 1 H), 5.80 (s, 1 H). – 13C{1H} NMR (50 MHz, CDCl3):
δ ϭ 21.0 (CH2), 23.9 (CH3), 27.0 (CH2), 28.1 (CH2), 30.9 (CH2),
35.1 (CH2), 41.1 (CH2), 58.6 (C), 125.4 (CH), 161.0 (C), 198.3 (C),
210.9 (C). – MS (EI, 70 eV); m/z (%): 193 (40) [M ϩ Hϩ], 192 (2)
[Mϩ], 174 (43), 164 (19), 136 (31), 121 (30), 82 (100). – IR (ATR):
ν˜ ϭ 2937 (s), 1704 (vs), 1661 (vs), 1209 (s) cm–1. – C12H16O3
(192.3): calcd. C 74.97, H 8.39; found C 74.72, H 8.37. – HRMS:
calcd. 193.1229; found 193.1230 [M ϩ Hϩ].
N. End, L. Macko, M. Zehnder, A. Pfaltz, Chem. Eur. J. 1998,
4, 818–824.
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J. Christoffers, A. Mann, J. Pickardt, Tetrahedron 1999, 55,
[8b]
5377–5388. –
1999, 1475–1479. –
Asymmetry 1999, 10, 1207–1215. –
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General Procedure 4 (GP4). – Transesterification: A mixture of
compound 4 (1 equiv.) and DMAP (3 equiv.) in absolute MeOH
or EtOH (50 equiv.) was heated in a sealed reaction flask to 50 °C
for 30 h. The mixture was diluted with MTB and filtered through
SiO2 (3 cm) to yield a mixture of starting material 4 and transesteri-
fied product 4Ј, which was analyzed by chiral GC.
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Acknowledgments
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[18c] D. Desmaele, J. dЈAngelo, C. Bois, Tetrahedron: Asymmetry
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft. We are also grateful
to Prof. S. Blechert and the Institut für Organische Chemie der
Technischen Universität Berlin for support. J. C. also thanks the
Deutsche Forschungsgemeinschaft for a fellowship.
1990, 1, 759–762. – [18d] A. Guingant, H. Hammami, Tetrahed-
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ron: Asymmetry 1991, 2, 411–414. –
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Received September 15, 1999
[O99529]
[1]
[1a]
Reviews:
E. D. Bergmann, D. Ginsburg, R. Pappo, Org.
[1b]
React. 1959, 10, 179–555. –
D. A. Oare, C. H. Heathcock,
Eur. J. Org. Chem. 2000, 701Ϫ705
705