Copper-catalyzed asymmetric Michael reactions with α-amino acid amides: Synthesis of an optically active piperidine derivative

Article abstract of DOI:10.1002/1099-0690(200205)2002:9<1505::AID-EJOC1505>3.0.CO;2-K

Quaternary stereocenters are obtained at room temperature in copper-catalyzed asymmetric Michael reactions with α-amino acid amides as chiral auxiliaries. L-Valine diethylamide was applied as a chiral auxiliary, and an optically active piperidine derivati

Full text of DOI:10.1002/1099-0690(200205)2002:9<1505::AID-EJOC1505>3.0.CO;2-K

FULL PAPER
Copper-Catalyzed Asymmetric Michael Reactions with α-Amino Acid Amides:
Synthesis of an Optically Active Piperidine Derivative
[a]
[a]
Jens Christoffers* and Heiko Scharl
Keywords: Asymmetric synthesis / Catalysis / C-C coupling / Copper / Michael additions
Quaternary stereocenters are obtained at room temperature
optical purity of the product was established by GLC after
in copper-catalyzed asymmetric Michael reactions with α-
cyclization to a hexahydroisoquinolonecarboxylate.
amino acid amides as chiral auxiliaries.
L-Valine diethyl-
amide was applied as a chiral auxiliary, and an optically
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
active piperidine derivative was prepared with 97% ee. The
2002)
Introduction
ketone (4) gave the optically active product 5 in 74% yield
after acidic hydrolysis. The reaction was performed at 23 °C
Asymmetric conjugate additions are valuable stereoselec- in acetone as solvent and the exclusion of moisture or air
tive CϪC bond forming reactions.[
1Ϫ3]
Metal-catalyzed was not necessary. The carbamate protective group of 5
Michael reactions are an important alternative to base cata- seemed to be stable under workup conditions (1  hydro-
lysis, since the chemoselectivity is improved in most chloric acid). The auxiliary could be recovered from the
[
4,5]
cases.
In the field of metal-catalyzed enantioselective aqueous layer by extraction. The absolute configuration of
Michael reactions the heterobimetallic catalysts developed the Michael reaction product was assigned as (S)-5.[
12Ϫ14]
by Shibasaki are presently defining the state-of-the-art.[
6,7]
Applying Shibasaki’s method tertiary stereocenters are gen-
erally formed with excellent selectivities at ambient temper-
ature, whereas low temperatures are required for the genera-
[8Ϫ11]
tion of quaternary stereocenters.
More problematic,
however, is the incompatibility of the Lewis acidic catalyst
with substrates containing donor groups like amino func-
tions or carbamate moieties. Recently, we reported the ap-
plication of α-amino acid dialkyl amides as chiral auxilia-
ries for copper-catalyzed asymmetric Michael reac-
[
12,13]
tions.
Herein we wish to prove the compatibility of our
method with substrates with carbamate functions. There-
fore, we have prepared an optically active piperidine
derivative bearing a quaternary stereocenter with 97% ee at
room temperature applying the method recently developed
in our laboratory.
Scheme 1. Copper-catalyzed asymmetric Michael reaction with -
Results and Discussion
valine diethylamide 2 as auxiliary: a) 2, cat. HCl, molecular sieves
˚
4
A, toluene, 50 °C, 16 h, 82%; b) 1. 10 mol % Cu(OAc)
2
·H
2
O, 4,
The acid-catalyzed conversion of β-ketocarboxylate 1 acetone, 23 °C, 16 h, 2. HCl/H
2
O (1 ), 0 °C, 2 h, 74%
with equimolar amounts of the auxiliary -valine diethyl-
amide 2 yielded the enamino ester 3 (82%) (Scheme 1).
Treatment of the Michael donor 3 with a catalytic amount
Derivatives had to be prepared in order to determine the
of copper(II) acetate and a small excess of methyl vinyl enantiopurity of the product 5. First of all we synthesized
the O-acetyl mandelic amide 7 by deprotection (95%) of 5
[
a]
Institut für Organische Chemie, Universität Stuttgart,
Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax: (internat.) ϩ49-711/685-4269
followed by conversion of the secondary amine 6 with O-
acetyl--mandelic acid and DCC (70% yield; Scheme 2).
Careful analysis of the H and C NMR spectra of 7,
1
13
E-mail: jchr@po.uni-stuttgart.de
Eur. J. Org. Chem. 2002, 1505Ϫ1508

WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0509Ϫ1505 $ 20.00ϩ.50/0
1505

J. Christoffers, H. Scharl
FULL PAPER
which was not to trivial due to rotamers of the amide moi- and a Bondex unβ column[15] (20 m ϫ 0.3 mm) with hydrogen car-
rier gas (0.4 bar). Column chromatography was accomplished on
Merck silica gel (Type 60, 0.063Ϫ0.200 mm) or ICN alumina
ety, showed that our material had a purity of at least of
9
5% de. Of course, we also prepared the epimeric mixture
(
Al
2 3
O 90, basic, activity stage I) using ethyl acetate (EA) and hex-
of 7 from racemic 5 for comparison. However, we were not
sure whether we might have lost the other diastereoisomer
during the purification. Therefore, we also cyclized piperid-
[16]
anes (PE) as solvents. (S)-(ϩ)-O-Acetylmandelic acid
and the
auxiliary 2[ were synthesized according to literature procedures.
13]
ine 5 to compound 8 (70%), which gave sufficient baseline- 1-tert-Butyl-3-methyl-4-oxopiperidine-1,3-dicarboxylate (1): A solu-
tion of Boc
solution of 3-methoxycarbonyl-4-oxopiperidinium chloride
6.57 g, 33.9 mmol) and K CO (2.34 g, 17.0 mmol) in MeOH (25
mL), and the resulting mixture was stirred for 16 h at 23 °C. After
all volatile materials had been removed under vacuum, the residue
2
O (7.41 g, 33.9 mmol) in MeOH (25 mL) was added to
resolution in GC on a chiral phase in a racemic sample.
Finally, the optical purity of compound 8 was determined
to be 97% ee. Cleavage of the carbamate protective group
in 8 yielded compound 9 (94%), which is a very interesting,
enantiopure building block with three different functionali-
ties for further transformations: a secondary amine, an en-
one, and a methyl ester.
a
(
2
3
was partitioned between CH
were separated and the aqueous layer extracted with CH
0 mL). After drying of the combined organic layers (MgSO
filtration, and removal of the solvent under vacuum, carbamate 1
8.52 g, 33.1 mmol, 98%) was obtained as a colorless, crystalline
material, m.p. 59 °C. Only the enol tautomer is observed in the
2
Cl
2
and H
2
O (40 mL, 1:1), the layers
Cl (3 ϫ
),
2
2
5
4
(
1
NMR spectra. H NMR (300 MHz, CDCl
3
): δ ϭ 1.48 (s, 9 H),
2
4
2
8
.37 (t, J ϭ 5.9 Hz, 2 H), 3.57 (t, J ϭ 5.9 Hz, 2 H), 3.78 (s, 3 H),
1
3
1
.06 (s, 2 H), 11.98 (s, 1 H). C{ H} NMR (75 MHz, CDCl
8.41 (CH ), 28.86 (CH ), 39.18 (CH ), 40.32 (CH ), 51.56 (CH
0.11 (C), 96.20 (C), 154.54 (CO), 170.09 (CO), 171.04 (CO). IR
3
): δ ϭ
3
2
2
2
3
),
Ϫ1
(
(
KBr): ν˜ ϭ 1701, 1678, 1633 cm . MS (70 eV, EI): m/z (%) ϭ 257
ϩ
ϩ
ϩ
1) [M ], 200 (66) [M Ϫ tBu], 168 (62) [M Ϫ MeOH Ϫ tBu].
(257.28): calcd. C 56.02, H 7.44, N 5.44; found C
6.12, H 7.43, N 5.32.
12 5
C H19NO
5
N-(4-tert-Butyloxycarbonyl-2-methoxycarbonyl-4-aza-1-cyclo-
hexenyl)-
L
-valine Diethylamide (3): -Valine amide 2 (2.12 g,
˚
7
.77 mmol), molecular sieves (8.0 g, 4 A), and conc. hydrochloric
acid (ca. 50 mg) were added to a solution of piperidone 1 (2.00 g,
.77 mmol) in toluene (20 mL). After stirring the reaction mixture
for 16 h at 50 °C and filtration, the residue was washed with
CH Cl , and the filtrate evaporated under vacuum. Chromato-
graphy on Al
7
2
2
2
O
3
[PE/EA 1:1, R
f
(SiO
2
) ϭ 0.25] gave enamine 3a
2
0
(
2.62 g, 6.36 mmol, 82%) as a colorless solid, m.p. 131 °C. [α]
ϩ94.1 (c ϭ 6.95 g dm , CHCl
D
ϭ
Ϫ3
1
3
). H NMR (300 MHz, CDCl
3
):
Scheme 2. Determination of the optical purity after derivatization:
δ ϭ 1.00 (d, J ϭ 6.7 Hz, 3 H), 1.01 (d, J ϭ 6.7 Hz, 3 H), 1.12 (t,
J ϭ 7.1 Hz, 3 H), 1.20 (t, J ϭ 7.1 Hz, 3 H), 1.47 (s, 9 H), 1.99Ϫ2.10
a) TFA, CH
CH Cl
6 h, 70%; d) TFA, CH
2 2
Cl , 23 °C, 16 h, 95%; b) acetylmandelic acid, DCC,
2
2
, 23 °C, 16 h, 70%; c) pyrrolidine, AcOH, CH
2 2
Cl , 23 °C,
(
m, 1 H), 2.22 (ddd, J ϭ 16.2, J ϭ 6.1, J ϭ 6.1 Hz, 1 H), 2.36 (dt,
1
2
Cl , 23 °C, 16 h, 94%
2
J ϭ 16.2, J ϭ 5.6 Hz, 1 H), 3.17Ϫ3.19 (m, 1 H), 3.27Ϫ3.31 (m, 1
H), 3.39Ϫ3.46 (m, 2 H), 3.59 (br. s, 2 H), 3.70 (s, 3 H), 4.08 (br. s,
1
3
1
3
H), 9.27 (d, J ϭ 9.2 Hz, 1 H). C{ H} NMR (75 MHz, CDCl
δ ϭ 12.86 (CH ), 14.67 (CH ), 17.61 (CH ), 19.98 (CH ), 26.34
), 28.45 (CH ), 32.29 (CH), 39.05 (CH ), 40.30 (CH ), 41.52
), 41.76 (CH ), 50.76 (CH ), 57.58 (CH), 79.78 (C), 89.00 (C),
3
):
Conclusion
3
3
3
3
(
CH
2
2
3
2
2
(
CH
2
3
In conclusion, the copper-catalyzed, auxiliary-mediated
Michael reaction has proved to be compatible with carba-
mate functions in the substrate and therefore superior to
lanthanide-based methods. The piperidine derivative 5 bear-
ing a quaternary stereocenter was obtained with 97% ee en-
antioselectivity at room temperature. In order to determine
the enantiopurity the bicyclic derivative 8 was prepared,
which yields the hexahydroisoquinolone 9 on a multigram
scale after deprotection. This compound is a very interest-
ing optically active chiral building block.
1
1
54.77 (CO), 155.86 (C), 168.96 (CO), 170.42 (CO). IR (KBr): ν˜ ϭ
Ϫ1
696, 1670, 1650, 1603, 1415, 1260, 1175 cm . MS (70 eV, EI):
ϩ
ϩ
ϩ
m/z (%) ϭ 411 (8) [M ], 354 (100) [M Ϫ tBu], 311 (50) [M
CONEt ]. C21 (411.54): calcd. C 61.29, H 9.06, N 10.21;
found C 61.21, H 9.01, N 10.05.
Ϫ
2
37 3 5
H N O
(
؉)-(S)-1-tert-Butyl-3-methyl-4-oxo-3-(3-oxobutyl)piperidine-1,3-
dicarboxylate (5): After stirring a mixture of enamine 3 (800 mg,
.94 mmol), Cu(OAc) ·H O (39 mg, 0.19 mmol) and acetone (5
1
2
2
mL) for 30 min at 23 °C, MVK 4 (409 mg, 5.84 mmol) was added,
and the mixture stirred for a further 16 h at 23 °C. All volatile
materials were removed under vacuum, the residue was diluted with
Ϫ3
hydrochloric acid (5 mL, 1 mol dm ) and stirred for 2 h at 0 °C.
Experimental Section
The mixture was extracted with CH Cl (2 ϫ 10 mL), and the com-
2
2
bined organic layers were washed with sat. NaHCO
). After filtration and evaporation of the solvent,
chromatography on SiO (PE/EA 2:1, R ϭ 0.21) yielded 5 as a
3
(2 ϫ 10 mL)
General Remarks: Chiral GC analysis was performed with a HRGC and dried (MgSO
Mega 2 series (Fisons instruments) with FID, a SP4270 integrator,
4
2
f
1506
Eur. J. Org. Chem. 2002, 1505Ϫ1508

Copper-Catalyzed Asymmetric Michael Reactions with α-Amino Acid Amides
FULL PAPER
2
0
colorless solid (473 mg, 1.44 mmol, 74%), m.p. 64 °C. [α]
D
ϭ ϩ26 (C), 73.69 (CH), 128.67 (CH), 129.39 (CH), 129.70 (CH), 133.79
Ϫ3
1
(
(
(
c ϭ 5.7 g dm , CHCl
3
). H NMR (300 MHz, CDCl
3
): δ ϭ 1.48
(C), 166.88 (CO), 170.38 (CO), 170.79 (CO), 203.74 (CO), 206.89
Ϫ1
s, 9 H), 1.89 (ddd, J ϭ 14.4, J ϭ 10.0, J ϭ 5.4 Hz, 1 H), 2.03Ϫ2.13 (CO). IR (neat): ν˜ ϭ 1745, 1730, 1675 cm . MS (70 eV, EI): m/z
ϩ
ϩ
m, 1 H), 2.13 (s, 3 H), 2.49 (dt, J ϭ 14.8, J ϭ 5.0 Hz, 2 H), (%) ϭ 403 (1) [M ], 343 (20) [M Ϫ CO Ϫ MeOH], 224 (90), 56
.59Ϫ2.76 (m, 2 H), 3.24 (br. s, 1 H), 3.41 (br. s, 1 H), 3.74 (s, 3 (100). C21 (403.43): calcd. 403.1631; found 403.1626
H), 4.02 (br. s, 1 H), 4.41 (d, J ϭ 13.4 Hz, 1 H). C{ H} NMR (HRMS). Data for the (R,S)-diastereoisomer epi-7 (resulting from
75 MHz, CDCl ): δ ϭ 25.24 (CH ), 28.24 (CH ), 29.91 (CH ), conversion of racemic 5, only a single signal set is observed):
), 39.61 (CH ), 43.25 (CH ), 51.01 (CH ), 52.58 (CH ),
0.57 (C), 80.64 (C), 154.06 (CO), 170.73 (CO), 205.12 (CO), 29.97 (CH
2
H25NO
7
13
1
(
3
2
3
3
1
3
1
3
6
2
7
5
8.64 (CH
2
2
2
2
3
C{ H} NMR (125 MHz, CDCl
3
): δ ϭ 20.79 (CH ), 25.25 (CH
2
), 44.12 (CH ), 47.73 (CH
3
2
),
),
3
), 38.22 (CH ), 38.59 (CH
2
2
2
Ϫ1
07.07 (CO). IR (KBr): ν˜ ϭ 1725, 1697, 1436 cm . MS (EI, 52.79 (CH
), 60.99 (C), 73.34 (CH), 128.44 (CH), 129.39 (CH),
(327.29): calcd. C 129.82 (CH), 133.34 (C), 166.88 (CO), 170.09 (CO), 170.52 (CO),
8.70, H 7.70, N 4.28; found C 58.78, H 7.71, N 4.21. 203.87 (CO), 206.82 (CO).
3
ϩ
0 eV), m/z (%) ϭ 327 (6) [M ]. C16H25NO
6
rac-1-tert-Butyl-3-methyl-4-oxo-3-(3-oxobutyl)piperidine-1,3- (؉)-(R)-3-tert-Butyl-1-methyl-8-oxo-3-azabicyclo[4.4.0]-6-decene-
dicarboxylate (rac-5): MVK 4 (699 mg, 9.97 mmol) was added to a
1,3-dicarboxylate (8): mixture of carbamate (2.00 g,
mixture of piperidone 1 (1.28 g, 4.99 mmol), FeCl ·6H
O (67 mg, 6.11 mmol), CH Cl (10 mL), pyrrolidine (370 mg, 5.19 mmol), and
.25 mmol), and CH Cl (3 mL). After stirring for 16 h at 23 °C,
AcOH (312 mg, 5.19 mmol) was stirred for 16 h at 23 °C. All vola-
all volatile materials were removed under vacuum and the residue tile materials were removed under vacuum, and the residue was
was chromatographed on SiO (PE/EA 2:1) to yield rac-5 (1.29 g,
chromatographed on SiO (PE/EA 2:1, R ϭ 0.22) to yield 8 as a
.95 mmol, 79%) as a colorless solid, m.p. 48 °C.
colorless oil (1.32 g, 4.28 mmol, 70%). [α]
A
5
3
2
2
2
0
2
2
2
2
f
2
0
3
D
ϭ ϩ152 (c ϭ 5.2 g
3 3
dm , CHCl ). H NMR (300 MHz, CDCl ): δ ϭ 1.47 (s, 9 H),
Ϫ3
1
(
S)-Methyl-4-oxo-3-(3-oxobutyl)piperidine-3-carboxylate (6): A so-
lution of piperidone 5 (700 mg, 2.14 mmol) in a mixture of CH Cl
6 mL) and TFA (3 mL) was stirred for 16 h at 23 °C. All volatile
materials were removed under vacuum and the residue partitioned
between sat. NaHCO (10 mL) and CH Cl (10 mL). The layers
were separated, and the aqueous layer was extracted with CH Cl
2 ϫ 10 mL). After drying (MgSO ), filtration, and evaporation of
the solvent, chromatography on SiO
yielded 6 as a colorless oil (464 mg, 2.02 mmol, 95%). [α]
1
.84 (td, J ϭ 14.3, J ϭ 5.5 Hz, 1 H), 2.29Ϫ2.47 (m, 4 H), 2.64 (d,
2
2
J ϭ 12.8 Hz, 1 H), 2.82 (br. s, 2 H), 3.75 (s, 3 H), 4.42 (br. s, 1 H),
(
13
1
4
.67 (d, J ϭ 13.4 Hz, 1 H), 5.98 (s, 1 H). C{ H} NMR (75 MHz,
CDCl ): δ ϭ 28.28 (CH ), 30.75 (CH ), 32.93 (CH ), 34.48 (CH ),
3.21 (CH ), 48.96 (C), 52.82 (CH ), 52.96 (CH ), 80.28 (C), 127.64
3
3
2
2
2
3
2
2
4
2
3
2
2
2
(
(
CH), 153.88 (C), 158.77 (CO), 172.02 (CO), 197.90 (CO). IR
KBr): ν˜ ϭ 1731, 1685, 1229, 1162, 1128 cm . MS (EI, 70 eV):
(
4
Ϫ1
2
(MeOH/EA 1:4, R
f
ϭ 0.19)
ϭ ϩ140
ϩ
5
m/z (%) ϭ 309 (6) [M ]. C16H23NO (309.36): calcd. 309.1576;
found 309.1576 (HRMS). GC: Bondex un β, temperature program:
3
8
2
0
D
Ϫ3
1
(
(
3 3
c ϭ 4.5 g dm , CHCl ). H NMR (300 MHz, CDCl ): δ ϭ 1.81
Ϫ1
min 100 °C isotherm, then 2 K min gradient to 200 °C: t
) ϭ 47.25 min, t (S-8) ϭ 47.52 min, 97% ee.
R
(R-
ddd, J ϭ 14.4, J ϭ 9.6, J ϭ 5.7 Hz, 1 H), 1.96 (s, 1 H), 2.11 (ddd,
R
J ϭ 14.6, J ϭ 9.4, J ϭ 5.3 Hz, 1 H), 2.13 (s, 3 H), 2.34Ϫ2.45 (m,
H), 2.50Ϫ2.65 (m, 3 H), 2.92 (ddd, J ϭ 12.7, J ϭ 11.5, J ϭ 3.8
Hz, 1 H), 3.35 (ddt, J ϭ 12.8, J ϭ 6.5, J ϭ 2.5 Hz, 1 H), 3.71 (dd,
(
(
؉)-(R)-Methyl-8-oxo-3-azabicyclo[4.4.0]-6-decene-1-carboxylate
9): A solution of amine 8 (180 mg, 0.582 mmol) in CH Cl (2 mL)
2
2
2
J ϭ 13.4, J ϭ 2.0 Hz, 1 H), 3.76 (s, 3 H). 13C{ H} NMR (75 MHz,
CDCl ): δ ϭ 25.35 (CH ), 29.89 (CH ), 38.55 (CH ), 42.85 (CH ),
7.86 (CH ), 52.61 (CH ), 55.79 (CH ), 62.30 (C), 171.93 (CO),
05.46 (CO), 207.40 (CO). IR (neat): ν˜ ϭ 1720 cm . MS (70 eV,
1
and TFA (1 mL) was stirred for 16 h at 23 °C. All volatile materials
were removed under vacuum, the residue partitioned between
CH
was extracted with CH Cl (2 ϫ 10 mL), and the combined organic
4
layers were dried (MgSO ). Filtration and evaporation of the sol-
vent gave 9 as a colorless oil (114 mg, 0.545 mmol, 94%). [α]
ϩ282 (c ϭ 1.3 g dm , CHCl
3
2
3
2
2
2 2 3
Cl (10 mL) and sat. NaHCO (10 mL). The aqueous layer
4
2
2
3
2
Ϫ1
2
2
ϩ
EI): m/z (%) ϭ 227 (10) [M ], 196 (14), 170 (26), 168 (37), 139
2
0
D
ϭ
(
(
100). C11
HRMS).
4
H17NO (227.26): calcd. 227.1158; found 227.1166
Ϫ3
1
3 3
). H NMR (300 MHz, CDCl ): δ ϭ
1
.88 (td, J ϭ 13.6, J ϭ 6.0 Hz, 1 H), 2.09 (br. s, 1 H), 2.25 (ddd,
(
S,S)-Methyl-1-(2-acetoxy-2-phenylacetyl)-4-oxo-3-(3-oxobutyl)
solution of the deprotected
piperidone 6 (104 mg, 0.456 mmol) in CH Cl (1 mL) was added
to a mixture of DCC (94 mg, 0.46 mmol) and O-acetyl--mandelic
acid (89 mg, 0.456 mmol) in CH Cl (1 mL). After stirring for 16 h
at 23 °C, the reaction mixture was chromatographed on SiO (PE/
EA 1:4, R ϭ 0.38) to yield amide 7 (130 mg, 0.322 mmol, 70%) as
a colorless oil. [α]2
J ϭ 13.8, J ϭ 4.8, J ϭ 3.1 Hz, 1 H), 2.31Ϫ2.50 (m, 3 H), 2.49 (d,
J ϭ 12.8 Hz, 1 H), 2.54 (ddd, J ϭ 14.4, J ϭ 6.0, J ϭ 2.1 Hz, 1 H),
piperidine-3-carboxylate (7):
A
2
2
2
.73 (td, J ϭ 12.2, J ϭ 3.4 Hz, 1 H), 3.23 (ddt, J ϭ 12.3, J ϭ 6.0,
J ϭ 1.6 Hz, 1 H), 3.64 (dd, J ϭ 12.8, J ϭ 1.6 Hz, 1 H), 3.79 (s, 3
13
1
2
2
H), 5.96 (d, J ϭ 1.9 Hz, 1 H). C{ H} NMR (75 MHz, CDCl
δ ϭ 30.63 (CH ), 34.41 (CH ), 34.73 (CH ), 46.93 (CH ), 49.60
), 57.14 (CH ), 126.82 (CH), 160.33 (C), 173.41
CO), 198.28 (CO). IR (neat): ν˜ ϭ 3430, 1735, 1680, 1600 cm
3
):
2
2
2
2
2
f
(
(
C), 52.78 (CH
3
2
0
Ϫ3
ϭ ϩ150 [c ϭ 5.2 g dm , CHCl
3
, (S,S)-diaster-
Ϫ1
D
.
eoisomer]. The NMR spectra show a doubled signal set due to
hindered rotation of the amide CϪN bond. H NMR (300 MHz,
CDCl
3
2
ϩ
3
MS (EI, 70 eV): m/z (%) ϭ 209 (100) [M ]. C11H15NO (209.24):
calcd. 290.1052; found 290.1052 (HRMS).
1
3
): δ ϭ 1.65Ϫ1.74 (m, 0.5 H), 1.83Ϫ2.01 (m, 1.5 H), 2.12 (s,
.5 H), 2.17 (s, 3 H), 2.26Ϫ2.49 (m, 2 H), 2.54Ϫ2.59 (m, 0.5 H),
.67Ϫ2.90 (m, 2 H), 3.27 (d, J ϭ 13.6 Hz, 0.5 H), 3.56Ϫ3.62 (m, 2
Acknowledgments
H), 3.74Ϫ3.88 (m, 2 H), 4.36 (d, J ϭ 13.9 Hz, 0.5 H), 4.73 (d, J ϭ This work was generously supported by Aventis Pharma Deutsch-
1
(
3.6 Hz, 0.5 H), 4.85 (d, J ϭ 8.9 Hz, 0.5 H), 6.26 (s, 0.5 H), 6.49 land GmbH, the Deutsche Forschungsgemeinschaft and the Fonds
s, 0.5 H), 7.41Ϫ7.46 (m, 5 H). 13C{ H} NMR (125 MHz, CDCl
1
): der Chemischen Industrie. Moreover, we thank Dr. P. Fischer for
3
rotamer 1: δ ϭ 20.78 (CH
3
), 25.19 (CH
2
), 29.89 (CH ), 38.53
3
), 52.63 (CH ), 60.40
3
helpful discussions of NMR spectra.
(
(
(
(
(
CH
2
), 38.85 (CH
2
), 44.34 (CH
2
), 48.52 (CH
2
C), 73.34 (CH), 128.39 (CH), 129.22 (CH), 129.70 (CH), 133.55
C), 166.88 (CO), 170.18 (CO), 170.69 (CO), 203.59 (CO), 206.89
[1]
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Received December 18, 2001
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1508
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