Asymmetric conjugate additions of TMSI promoted monoorganocuprate reagents, Li[RCuI], to various N-enoyl oxazolidinones

Article abstract of DOI:10.1016/S0040-4039(02)00646-9

Diastereoselective conjugate additions to different α,β-unsaturated N-acyl oxazolidinones using various monoorganocuprate reagents, Li[RCuI], are described. The TMSI activated conjugate addition reactions provided high yields (80-98%) and reversed major d

Full text of DOI:10.1016/S0040-4039(02)00646-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3693–3697
Asymmetric conjugate additions of TMSI promoted
monoorganocuprate reagents, Li[RCuI], to various N-enoyl
oxazolidinones†
Patrick Pollock,‡ Jesse Dambacher, Robert Anness and Mikael Bergdahl*
Department of Chemistry, San Diego State University, San Diego, CA 92182-1030, USA
Received 4 March 2002; accepted 27 March 2002
Abstract—Diastereoselective conjugate additions to different a,b-unsaturated N-acyl oxazolidinones using various
monoorganocuprate reagents, Li[RCuI], are described. The TMSI activated conjugate addition reactions provided high yields
(80–98%) and reversed major diastereomers (70–96% de) compared to the conventional copper(I)-promoted additions of Grignard
reagents or the addition of Li[RCuI] to precomplexed MgBr2/imides. © 2002 Elsevier Science Ltd. All rights reserved.
Organocopper compounds are among the most ver-
satile reagents for CꢀC bond formations.1 Additives
have been used with organocopper chemistry for some
time, one of the most notable reagents being chloro-
trimethylsilane (TMSCl). This additive was originally
employed to trap intermediate enolates,2 but was soon
discovered to increase the reactivity of cuprates in
1,4-addition reactions.3 The discovery that TMSI is a
better activator than TMSBr or TMSCl for
monoorganocuprate reagents, RCu(LiI),4 or more
appropriately written as Li[RCuI],5 has provided sub-
stantial evidence that this reagent is a powerful tool for
conjugate additions to a,b-unsaturated carbonyl com-
We now report conjugate additions of TMSI-promoted
monoorganocuprate reagents Li[RCuI] to chiral N-
enoyl derived oxazolidinones.14 The opposite p-facial
selectivity is obtained when employing the Li[RCuI]/
TMSI reagent system than with the copper-promoted
Grignard reagents, zirconium reagents, and TMSCl-
promoted Gilman reagents to Koga’s g-butyrolactam.6c
The yield of the products ranges from 80 to 98%
(Tables 1–3) using the Li[RCuI]/TMSI system. The
stereoselectivity (70–96% de) of the 1,4-products is
highly dependent on the specific oxazolidinone and the
copper reagent employed.
pounds.6
Asymmetric
conjugate
additions
of
The diastereomeric ratio (de) was determined by 1H
NMR spectroscopy and further compared to the enan-
tiomeric ratio (ee) obtained using optical rotation mea-
surements of the known carboxylic acids10 or the
corresponding alcohols15 after chemical removal of the
chiral auxiliary. The highest stereoselectivities (96–92%
de) were obtained using the N-enoyl phenylglycine-
derived oxazolidinones 1 and 2 employing the Li[R-
CuI]/TMSI reagent (Table 1). Conjugate addition of
PhMgCl/CuI (entry 5) to substrate 1 gave 90% de of 5b
as the major diastereomer. In contrast, the opposite
major diastereomer 5a was obtained in 92% de when
applying the Li[PhCuI]/TMSI reagent to substrate 1
(entry 4). Conducting a copper reaction using cinna-
mate 3 or Li[MeCuI]/TMSI proved to be slightly less
selective in the conjugate addition reactions (entry 10).
organocopper reagents to prochiral substrates using
chiral heterocuprates7 and chiral ligands8 has expanded
dramatically over the last decade. Chiral auxiliaries in
conjugate additions of organocopper reagents have also
been explored for some time, e.g. Oppolzer’s camphor
derivatives,9 and Koga’s g-butyrolactam.10 Evans’ oxa-
zolidinone has been used extensively due to the excel-
lent levels of stereoselectivity in asymmetric aldol
reactions.11 Copper(I)-promoted asymmetric conjugate
additions of Grignard reagents12 and zirconium
reagents13 have been reported to add in a 1,4-fashion to
N-enoyl derived oxazolidinones with high yields and
stereoselectivities.
* Corresponding author. E-mail: bergdahl@sciences.sdsu.edu
In memory of Professor Martin Nilsson, Chalmers University of
†
The diastereomeric ratio obtained using the copper-pro-
moted Grignard reagent (or MgBr2, entry 2) is most
likely caused by the substrate reacting in the syn-s-cis
Technology, Sweden.
‡ Present address: Eli Lilly & Co. Indianapolis, IN 46285, USA.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00646-9

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P. Pollock et al. / Tetrahedron Letters 43 (2002) 3693–3697
Table 1. Conjugate additions to phenylglycine-derived oxazolidinones 1–3
Ph
Ph
O
Ph
O
O
O
a
O
1) "RCu"
THF, 4 h, -78 °C
2) Et3N, NH4Cl(aq)
H
H
H
R
R
N
N
N
O
R1
R1
R1
O
O
O
1-3
b
Entry
Substrate
Reagent (RCu)
Product
Ratio (a:b)b
Yield (%)a
1
2
3
4
5
6
7
8
9
1; R1=Me
1; R1=Me
1; R1=Me
1; R1=Me
1; R1=Me
1; R1=Me
2; R1=n-Bu
2; R1=n-Bu
3; R1=Ph
3; R1=Ph
Li[n-BuCuI]/TMSI
Li[n-BuCuI]/MgBr2
Li[n-BuCuI]/MgBr2/TMSI
Li[PhCuI]/TMSI
PhMgCl/CuI
PhMgCl/CuI/TMSI
Li[PhCuI]/TMSI
Li[MeCuI]/TMSI
Li[n-BuCuI]/TMSI
Li[MeCuI]/TMSI
4
4
4
5
5
5
6
4
6
5
98:2 (4S:4R)
3:97 (4S:4R)
98:2 (4S:4R)
96:4 (5R:5S)
5:95 (5R:5S)
5:95 (5R:5S)
97:3 (6R:6S)
91:9 (4R:4S)
92:8 (6S:6R)
92:8 (5S:5R)
83
77c
80d
83
74e
51e
83
84
96
10
80
a Based on isolated and purified material (a+b).
b Ratio determined from the crude 1H NMR spectrum.
c Precomplexed MgBr2OEt2 (1 equiv.) and imide 1 at +20°C.
d MgBr2OEt2 added to RCu at −78°C.
e CuI (1 equiv.) versus PhMgCl.
Table 2. Asymmetric conjugate addition to valine-derived oxazolidinone 7
O
O
O
1) "RCu"
THF, 4 h, -78 °C
H
H
H
R
R
N
N
N
O
O
O
O
2) Et3N, NH4Cl(aq)
Me
Me
Me
O
O
a
7
b
Entry
Reagent (RCu)
Product
Ratio (a:b)b
Yield (%)a
11
12
13
14
Li[n-BuCuI]/TMSI
n-BuMgBr/CuI
Li[t-BuCuI]/TMSI
Li[PhCuI]/TMSI
8
8
9
95:5 (8R:8S)
88
21:79 (8R:8S)
85:15 (9S:9R)c
93:7 (10S:10R)
75d
92
10
92
a Based on isolated and purified material (a+b).
b Ratio determined from the crude 1H NMR spectrum.
c R/S assignment based on analogy.
d CuI (1 equiv.) versus BuMgBr.
conformation via chelation by RMgX to the carbonyl
oxygens within the imide (Scheme 1).12c
complexation between MgBr2 and imide 1 has a
tremendous effect on the conjugate addition of Li[Bu-
CuI] (entry 2). The precomplexed MgBr2/imide and the
Grignard reagents seem to react with the imide adopt-
ing the syn-s-cis conformation.
A similar chelation model has been proposed for the
copper-promoted conjugate addition of alkyl-zirconium
reagents to N-acyl oxazolidinones.13a The TMSI-pro-
moted additions of monoorganocuprates seem instead
to undergo an initial copper-p complex formation fol-
lowed by an alkyl transfer via the more stable non-
chelated anti-s-cis conformation. A large difference in
energy between the two conformations is most likely
caused by the electrostatic repulsion between the car-
bonyl oxygen atoms in the non-chelated structure.
Addition of scavenger chelating agents to the
organocopper reagent such as magnesium bromide
(entry 3) or lithium iodide (8 equiv.) did not appear to
affect the de nor the yield for the TMSI activated
additions of Li[RCuI]. On the other hand, the ‘forced’
The copper-promoted Grignard reagent additions in
THF were faster than the analogous additions using
Li[RCuI]/TMSI in THF. Thus, quenching a Li[PhCuI]/
TMSI reaction at −78°C after 2 h showed 50% con-
sumption of substrate
1 while the addition of
PhMgCl/CuI was complete within 2 h at −78°C. A
relatively slow reaction at −78°C is most likely an
important factor in obtaining a high de. In comparison,
the additions of Li[MeCuI]/TMSI to substrates 2 or 3
gave 82–84% de of products 4 and 5, while the corre-
sponding MeMgBr/CuBr addition to the same cinna-
mate 3 has been reported to give only 48% de.12d

P. Pollock et al. / Tetrahedron Letters 43 (2002) 3693–3697
3695
Table 3. Asymmetric conjugate addition to phenylalanine-derived oxazolidinones 11–13
Ph
Ph
Ph
H
O
O
O
b
1) "RCu"
THF, 4 h, -78 °C
2) Et3N, NH4Cl(aq)
H
H
R
R
N
N
N
+
O
O
O
R1
R1
R1
O
O
O
11-13
a
Entry
Substrate
Reagent (RCu)
Product
Ratio (a:b)b
Yield (%)a
15
16
17
18
19
20
21
22
23
24
11; R1=Me
11; R1=Me
11; R1=Me
11; R1=Me
11; R1=Me
12; R1=n-Bu
12; R1=n-Bu
12; R1=n-Bu
13; R1=Ph
13; R1=Ph
Li[n-BuCuI]/TMSI
Li[n-BuCuI]/MgBr2
Li[PhCuI]/TMSI
Li[t-BuCuI]/TMSI
PhMgCl/CuI
Li[PhCuI]/TMSI
Li[MeCuI]/TMSI
Li[MeCuI]/BF3OEt2
Li[n-BuCuI]/TMSI
Li[MeCuI]/TMSI
14
14
15
16
15
17
14
14
17
15
85:15 (14R:14S)
50:50 (14R:14S)
87:13 (15S:15R)
87:13 (16S:16R)d
45:55 (15S:15R)
88:12 (17S:17R)
82:18 (14S:14R)
–
98
71c
86
85
80e
87
86
0f
90:10 (17R:17S)
86:14 (15R:15S)
91
83
a Based on isolated and purified material (a+b).
b Ratio determined from the crude 1H NMR spectrum.
c Precomplexed MgBr2OEt2 (1 equiv.) and imide 11 at +20°C.
d R/S assignment based on X-ray structure of pure 16a.
e CuI (1 equiv.) versus PhMgCl.
f 94% recovery of 12.
I
SiMe3
Me
Ph
Ph
O
Ph
O
I
O
O
H
H
H
RMgX/CuX
Cu
Li[RCuI]/TMSI
N
N
N
R
Cu
X
O
O
Me
Me
O
O
Mg O
R
1; anti-s-cis
syn-s-cis
X
Me
R
Ph
O
Ph
H
Me3SiO
R
H
N
N
O
O
Me
O
Mg
X
O
Scheme 1.
compared to the 92% de of 5a obtained using the
phenylglycine-derived oxazolidinone 1 (entry 4). As
expected, excess of the opposite diastereomer (8b, 58%
de) was obtained using copper-promoted addition of
BuMgBr (entry 12), while the TMSI activated conju-
gate addition of Li[BuCuI] provided an excess of the
other diastereomer (8a, 90% de).
Using TMSI as an additive is crucial for the successful
addition of the noticeably more soluble Li[RCuI]
reagent in THF at −78°C.6 On the other hand, TMSI
does not influence the stereoselectivity when applying
the copper(I)-promoted PhMgCl to crotonate 1 (entry
6).
We were also interested in the substituent effects of the
chiral auxiliary group on the stereoselectivity using the
organocopper reagents. The capacity of the phenyl-
glycine-derived auxiliary using the Li[RCu]I/TMSI was
compared to the corresponding valine- and phenylala-
nine-derived oxazolidinones.
We initially paid some attention to the phenylalanine-
derived oxazolidinones 11–13. Employing the TMSI-
promoted organocopper reagents provided superior
diastereomeric ratios compared to the copper-promoted
Grignard reagent additions to the same substrates
(Table 3). TMSI-promoted addition of Li[PhCuI] to 11
gave 74% de of 15 with 15a as the major isomer (entry
17), while the corresponding copper-promoted addition
of PhMgCl in the presence of 1 equiv. CuI showed a
complete lack of p-facial selectivity (entry 19).16 The
The valine-derived auxiliary 7 is slightly less efficient at
blocking one p-face using the Li[RCuI]/TMSI reagent
in conjugate addition reactions. Conjugate addition of
Li[PhCuI]/TMSI to 7 (entry 14) gave 10a in 86% de

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P. Pollock et al. / Tetrahedron Letters 43 (2002) 3693–3697
Acknowledgements
Li[MeCuI]/TMSI protocol was compared to Li[Me-
CuI]/BF3OEt2 under identical reaction conditions
(entries 21–22). Thus, the TMSI-promoted reaction
gave 86% of 14, while the presence of BF3OEt2 did not
give any conjugate addition product 14. Li[BuCuI]
underwent a smooth conjugate addition at −78°C to the
precomplexed MgBr2/imide 11 (entry 16) in 71%. This
lack of stereoselectivity in the conjugate addition seems
consistent using chelating reagents and the N-enoyl
phenylalanine-derived oxazolidinone.
We thank Dr. Andrew L. Cooksy, Dr. Le Roy Lafferty
and Dr. Sam Somanathan for technical assistance.
Funding was provided by RSCA and the FGIA SDSU
Foundation.
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In conclusion, the Li[RCuI]/TMSI reagent is a very
powerful tool in asymmetric conjugate additions to
N-enoyl oxazolidinones. In particular, the phenyl-
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1
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methylheptanol20 in 82% ee.

P. Pollock et al. / Tetrahedron Letters 43 (2002) 3693–3697
3697
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17. CuI purified via its dimethylsulfide complex, see: House,