Regioselective formation of endo- and exo- cyclic enamines: Both enantiomeric products accessible by the same chiral auxiliary

Article abstract of DOI:10.1055/s-2003-37513

The copper-catalyzed conversion of exo-cyclic enamines 4a-c with methyl vinyl ketone (2) yields spirocyclic products 6a-c in a sequence of Michael and aldol reaction. The application of the chiral auxiliary L-valine diethylamide results in the formation o

Full text of DOI:10.1055/s-2003-37513

LETTER
493
Regioselective Formation of endo- and exo-Cyclic Enamines: Both Enantio-
meric Products Accessible by the Same Chiral Auxiliary
R
egioselec
e
tive Forma
n
tionof endo
-
s
a
nd exo-Cyclic
C
E
namines hristoffers,* Burkard Kreidler, Heiko Oertling, Sven Unger, Wolfgang Frey
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
Fax +49(711)6854269; E-mail: jchr@po.uni-stuttgart.de
Received 2 January 2003
In order to utilize new substrates as Michael donors, we
prepared exo-cyclic enamines 4a and 4b from the corre-
sponding α-acetyl butyrolactone and α-acetyl valero-
lactam4 and the respective L-valine dialkylamide in acid-
Abstract: The copper-catalyzed conversion of exo-cyclic enamines
4a–c with methyl vinyl ketone (2) yields spirocyclic products 6a–c
in a sequence of Michael and aldol reaction. The application of the
chiral auxiliary L-valine diethylamide results in the formation of
quaternary stereocenters with high enantiomeric excess. The con- catalyzed reactions. Compound 4a was obtained in 85%
yield as a mixture of Z- and E-isomer (ratio E/Z = 1:3),5
figuration of intermediate imine 5a is determined to be S. Thus, exo-
cyclic enamines 4 yield S-configured spiroketones 6, whereas, as
product 4b in 48% yield as the Z-isomer only. Derivative
shown for spiroketone ent-6c, reaction of endo-cyclic enamines
4b is unstable towards SiO2 and, thus, was purified by
such as 1 generates the opposite configuration in the products ap-
chromatography on basic alumina. The preparation of
plying the same auxiliary L-valine diethylamide 9.
exo-cyclic enamine 4c from diketone 7 is outlined in
Key words: chiral auxiliaries, copper, Michael additions, regio-
Scheme 3 and will be discussed later.
selectivity, stereoselectivity
Copper-catalyzed conversion of all three enamines 4a–c
with 2 in acetone at ambient temperature surprisingly
yielded the spirocyclic compounds 5a–c as the only prod-
Recently, we have introduced a new procedure for the
construction of quaternary stereocenters1 by asymmetric
Michael reactions2 at ambient temperature applying
α-amino acid amides as chiral auxiliaries.3 Typical sub-
strates for the reaction are β-ketoesters and β-diketones.
The auxiliary L-valine diethylamide is introduced by
Brønsted acid catalyzed enamine formation. Scheme 1
gives an example: The endo-cyclic enamine 1 (whose
preparation is shown in Scheme 3 and discussed later) is
converted in a copper-catalyzed reaction with methyl vi-
nyl ketone (2). Subsequent acidic hydrolysis affords prod-
uct 3 with 96% ee selectivity. The procedure is very easy
to handle, since inert or anhydrous conditions are not
required. Acetone is used as the solvent. Furthermore,
construction of quaternary stereocenters at ambient temp-
erature is an outstanding achievement.
ucts (Scheme 2). Obviously, in case of exo-cyclic enam-
ines the reaction sequence did not stop at the stage of the
Michael reaction, but a subsequent aldol-type spiroannu-
lation proceeded. Since the spirolactam6 and -lactone moi-
ety is an important structural motif in biologically relevant
compounds, spirocyclization to imines 5a and 5b is cer-
tainly of interest.
Scheme 2 Formation of spirocyclic imines 5a–c from exo-cyclic
enamines 4a–c as well as conversion of 3, 5 to spiroketones 6a–c for
GC analysis. Reagents and conditions: a) Cu(OAc)2·H2O (5–10
mol%), 2 (1.5–3 equiv), acetone, 16 h, 23 °C; b) conditions for 5a:
0 °C, 5 h, H2SO4–H2O; conditions for 5b: 23 °C, 16 h, HCl–acetone
(1:1); conditions for 5c: 23 °C, 5 h, HCl–H2O; for details see Table 1;
c) 1. concd H2SO4 (10 equiv), 2. H2O (ice).
Scheme 1 Copper-catalyzed, auxiliary-assisted asymmetric Mi-
chael reaction. Reagents and conditions: a) 1. Cu(OAc)2⋅H2O (5
mol%), 2 (2 equiv), 16 h, 23 °C, acetone, 2. HCl (1 moldm–3), 0 °C,
2–3 h.
Products 5a–c bear the imine function in a neopentyl situ-
ation, hence, it exhibits reasonable stability towards hy-
drolysis. Only derivative 5a7 was hydrolyzed to
spirolactone 6a on a preparative scale (Scheme 2,
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0493,0496,ftx,en;G00103ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

494
J. Christoffers et al.
LETTER
Table 1 Spirocyclic Imines 5 Derived from Enamines 4 and Hydrolysis to Ketones 6
4
n
0
1
1
X
R
5
de (%)
>99
>95
86
Yield (%)
6
ee (%)
>99
>95
87
Yield (%)
4a
4b
4c
O
Me
Et
Et
5a
5b
5c
54
37
46
6a
6b
6c
56
a
NCH2Ph
CH2
–
a
–
a Analytical scale only.10
Table 1).8,9 Compounds 5b and 5c were hydrolyzed to 6b yield. Investigations of regioselective spirocyclizations
and 6c only on an analytical scale10 in order to establish are currently under way and will be published elsewhere.
the optical purities of these derivatives by GLC on a chiral The constitution of 6c was confirmed by X-ray single
phase (6a: >99% ee, 6b: >95% ee, 6c: 87% ee). The rela- crystal analysis11 (Figure 2).
tive configuration of spirocyclic derivative 5a was estab-
From GLC on chiral phase it was deduced that the
spiroketone 6c derived from imine 5c is the enantiomer of
the product ent-6c derived from Michael addition product
lished by X-ray single crystal analysis11 to be S*,S*
(Figure 1).
Since the configuration of the auxiliary L-valine dimethyl- 3 (Scheme 2). Thus, conversion of the endo-cyclic ena-
amide is known to be S, it was proved that the quaternary mine 1 and the exo-cyclic enamine 4c results in comple-
stereocenter in product 5a is S-configured. In analogy, we mentary absolute configuration of the quaternary stereo-
also conclude this absolute configuration for imines 5b,c centers in products 3 and 5c. The configuration achieved
derived from enamines 4b,c and also for the spiro com- by conversion of endo-cyclic enamines like 1, which had
pounds 6.12 In case of spirolactone 6a, quantitative enan- been established earlier,3b is complementary to the config-
tiomeric purity was established: only one peak was uration achieved at conversion of exo-cyclic enamines
observed by GLC while the peak of the other enantiomer like 4c. This result is of particular interest, since the same
appeared after addition of about 0.5% of the respective ra- enantiomer of the auxiliary L-valine diethylamide 9 was
cemic material.13,14
applied.
The optical purity of product 3 could not be established di- The selective construction of S- and R-configured quater-
rectly by GLC on a chiral phase because of lack of base- nary stereocenters applying the same enantiomer of the
line resolution. However, separation of the enantiomers auxiliary requires regioselective formation of endo- and
was achieved after spirocyclization with concentrated exo-cyclic enamines. In the case of diketone 7, we have
H2SO4 (Scheme 2), yielding spirocycle ent-6c (being R- solved the problem as shown in Scheme 3: Acid-catalyzed
configured). However, apart from β-ketospirocycle ent-6c direct enamine formation gives the endo-cyclic product 1
also the regioisomeric 1,5-dicarbonyl-constituted spirocy- in 63% yield with quantitative selectivity. Conversion of
cle, as stated by NMR spectroscopy, was isolated in 21% the new borate-betaine 8 with auxiliary 9 according to a
known procedure15 gives the exo-cyclic derivative 4c in
87% yield as the kinetic product together with a small
amount of 1 (ratio 4c:1 = 97.5:2.5).
Figure 1 ORTEP view of the spirocyclic compound 5a.
Figure 2 ORTEP view of the spirocyclic ketone 6c.
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LETTER
Regioselective Formation of endo- and exo-Cyclic Enamines
495
Acknowledgment
This work was generously supported by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie. H. O. thanks
the Graduiertenkolleg ‘Synthetische, mechanistische und reaktions-
technische Aspekte von Metallkatalysatoren’ and B. K. the Landes-
graduiertenförderung Baden-Württemberg for fellowships. We are
deeply indebted to Prof. Joachim Pickardt, Technische Universität
Berlin, for X-ray crystallographic analysis of compound 5a, and we
acknowledge Dr. Angelika Baro, Universität Stuttgart, for her assi-
stance in preparing this manuscript.
References
(1) Reviews: (a) Christoffers, J.; Mann, A. Angew. Chem. Int.
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(2) Reviews: (a) Krause, N.; Hoffmann-Röder, A. Synthesis
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771. (f) d’Angelo, J.; Desmaele, D.; Dumas, F.; Guingant,
A. Tetrahedron: Asymmetry 1992, 3, 459.
Scheme 3 Regioselective enamine formation. Reagents and condi-
tions: a) BF3⋅OEt2 (1.5 equiv), CH2Cl2, 23 °C, 16 h, recrystallization
from Et2O; b) compound 9 (1 equiv), toluene, molecular sieves 4 Å,
cat. HCl; c) compound 9 (3 equiv), MeCN, 0 °C, 2 h, mixture of 4c
and 1 (97.5:2.5).
At elevated temperatures and upon exposure to Brønsted
acidic reaction conditions, the ratio 4c/1 shifts towards the
thermodynamic product 1. The borate complex 8 is ob-
tained as a crystalline material by simply stirring ketone 7
with BF3⋅OEt2, subsequent removal of all volatile materi-
als under high vacuum and recrystallization from Et2O.
An ORTEP representation of the X-ray single crystal
analysis of 811 is shown in Figure 3. The bonding situation
in the planar six-membered ring borate is symmetrical:
both B–O as well as both carbonyl C–O distances are
equal within the experimental error. Moreover, the
bond lengths of C(1)–C(2) and C(2)–C(3) are found to be
identical (1.38 Å) and they represent a bonding order of
about 1.5.
(3) (a) Christoffers, J.; Mann, A. Angew. Chem. Int. Ed. 2000,
39, 2752; Angew. Chem. 2000, 112, 2871. (b) Christoffers,
J.; Mann, A. Chem.–Eur. J. 2001, 7, 1014. (c) Christoffers,
J.; Scharl, H. Eur. J. Org. Chem. 2002, 1505.
(4) Christoffers, J.; Werner, T.; Unger, S.; Frey, W. Eur. J. Org.
Chem. 2003, 425.
(5) (Z)-N-[1-(Tetrahydro-2-furanon-3-ylidene)ethyl]-L-
valine dimethylamide (4a). To a solution of α-acetyl-γ-
butyrolactone (445 mg, 3.47 mmol), L-valine dimethylamide
(500 mg, 3.47 mmol) and molecular sieves (4 Å) in toluene
(4 mL) was added a drop of trifluoromethanesulfonic acid,
and the mixture was heated at 55 °C for 16 h. The reaction
mixture was filtered with CH2Cl2 and the solvent was
evaporated. The residue was purified by chromatography on
SiO2 (EtOAc–MeOH, 20:1, Rf 0.24) to give 4a as a colorless
oil (750 mg, 2.95 mmol, 85%), [α]D20 +160 (c 7.5, CHCl3).
1H NMR (CDCl3, 300 MHz): δ (ppm) = 1.01 (d, J = 6.6 Hz,
3 H), 1.03 (d, J = 5.9 Hz, 3 H), 1.88 (s, 3 H), 2.10 (dq,
J = 13.5 Hz, J = 6.8 Hz, 1 H), 2.82 (t, J = 7.9 Hz, 2 H), 2.98
(s, 3 H), 3.10 (s, 3 H), 4.14 (dd, J = 6.5 Hz, J = 9.1 Hz, 1 H),
4.26 (t, J = 8.0 Hz, 2 H), 8.61 (br d, J = 8.9 Hz, 1 H).
13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) = 16.85 (CH3),
18.02 (CH3), 19.65 (CH3), 26.53 (CH2), 31.76 (CH), 36.03
(CH3), 37.02 (CH3), 59.03 (CH), 65.04 (CH2), 86.82 (C),
155.06 (C), 171.50 (C), 173.77 (C). In the 13C NMR
spectrum a second set of signals was observed which was
assigned to the E-isomer of 4a (ratio E/Z = 1:3 by integration
of the NH resonance in the 1H NMR spectrum): 13C{1H}
NMR (CDCl3, 75 MHz): δ (ppm) = 12.78 (CH3), 17.48
(CH3), 19.44 (CH3), 26.17 (CH2), 32.62 (CH), 35.77 (CH3),
37.21 (CH3), 56.14 (CH), 63.24 (CH2), 89.25 (C), 153.68
(C), 171.67 (C), 172.68 (C). IR (ATR): 3285 (w, br), 2964
(s), 1690 (vs), 1646 (vs), 1611 (s), 1229 (vs), 1026 (s) cm–1.
HRMS calcd for C13H22N2O3: 254.1630. Found: 254.1636
[M+].
Figure 3 ORTEP view of the borate complex 8.
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LETTER
(6) (a) Andrews, D. M.; Carey, S. J.; Chaignot, H.; Coomber, B.
A.; Gray, N. M.; Hind, S. L.; Jones, P. S.; Mills, G.;
Robinson, J. E.; Slater, M. J. Org. Lett. 2002, 4, 4475.
(b) Tsujimoto, T.; Ishihara, J.; Horie, M.; Murai, A. Synlett
2002, 399. (c) Ishihara, J.; Horie, M.; Shimada, Y.; Tojo, S.;
Murai, A. Synlett 2002, 403. (d) Hughes, R. C.; Dvorak, C.
A.; Meyers, A. I. J. Org. Chem. 2001, 66, 5545. (e) Enders,
D.; Teschner, P.; Raabe, G.; Runsink, J. Eur. J. Org. Chem.
2001, 4463.
mmol, 56%), mp 66 °C, [α]D20 = +115 (c 1.5, CHCl3), >99%
ee; [α]D20 +107 (c 3.5, EtOH), >99% ee.12 1H NMR (CDCl3,
500 MHz): δ (ppm) = 2.00–2.05 (m, 1 H), 2.03 (s, 3 H), 2.11
(dt, J = 12.8 Hz, J = 8.5 Hz, 1 H), 2.30 (dt, J = 19.0 Hz,
J = 5.7 Hz, 1 H), 2.44 (ddd, J = 5.4 Hz, J = 6.6 Hz, J = 12.2
Hz, 1 H), 2.71 (ddd, J = 3.7 Hz, J = 7.2 Hz, J = 10.9 Hz, 1
H), 2.75 (dt, J = 12.2 Hz, J = 6.0 Hz, 1 H), 4.34–4.44 (m, 2
H), 5.9 (sextet, J = 1.0 Hz, 1 H). 13C{1H} NMR (CDCl3, 50
MHz): δ (ppm) = 24.41 (CH3), 27.96 (CH2), 30.79 (CH2),
32.65 (CH2), 52.66 (C), 65.95 (CH2), 124.31 (CH), 164.08
(C), 175.64 (C), 194.27 (C). IR (ATR): 2923 (s), 1766 (vs),
1655 (vs), 1630 (s), 1376 (s), 1217 (s), 1185 (vs), 1137 (s),
1060 (s), 1015 (vs), 985 (s) cm–1. HRMS calcd for C10H12O3:
180.0786. Found: 180.0781 [M+]. Anal. Calcd for C10H12O3:
C, 66.65; H, 6.71. Found: C, 66.82; H, 6.73.
(7) (S,S)-N-(8-Methyl-1-oxo-2-oxaspiro[4.5]dec-7-en-6-
ylidene)-L-valine dimethylamide (5a). A solution of 4a
(304 mg, 1.20 mmol) and Cu(OAc)2·H2O (12.0 mg, 0.060
mmol) in acetone (5 mL) was stirred at r.t. for 1 h. After
addition of 2 (0.17 g, 2.4 mmol), the reaction mixture was
stirred for 16 h. All volatile materials were removed under
high vacuum and the crude product was purified by
chromatography on SiO2 (EtOAc, Rf 0.26) to give 5a as a
colorless solid (197 mg, 0.643 mmol, 54%), mp 87–89 °C,
[α]D20 +15 (c 2.5, CHCl3). 1H NMR (CDCl3, 400 MHz): δ
(ppm) = 0.85 (d, J = 6.5 Hz, 3 H), 0.95 (d, J = 6.7 Hz, 3 H),
1.76–1.84 (m, 1 H), 1.91 (s, 3 H), 2.10–2.42 (m, 6 H), 2.85
(s, 3 H), 3.03 (s, 3 H), 3.98 (d, J = 9.8 Hz, 1 H), 4.28–4.42
(m, 2 H), 6.26 (br s, 1 H). 13C{1H} NMR (CDCl3, 50 MHz):
δ (ppm) = 19.46 (CH3), 20.57 (CH3), 24.43 (CH3), 27.96
(CH2), 30.96 (CH2), 31.27 (CH), 34.34 (CH2), 36.20 (CH3),
37.11 (CH3), 51.02 (C), 65.31 (CH2), 73.56 (CH), 114.43
(CH), 152.92 (C), 165.06 (C), 171.59 (C), 178.72 (C). IR
(ATR): 2961 (s), 2931 (s), 1772 (vs), 1635 (vs), 1386 (s),
1216 (s), 1184 (vs), 1030 (s) cm–1. HRMS calcd for
C17H26N2O3: 306.1943. Found: 306.1945. Anal. Calcd for
C17H26N2O3: C, 66.64; H, 8.55; N, 9.14. Found: C, 66.27; H,
8.17; N, 8.96.
(9) Compound 6a was reported before with higher optical
rotation of [α]D20 +149 (c 1.36, EtOH) despite lower optical
purity (86% ee), see: Felk, A.; Revial, G.; Viossat, B.;
Lemoine, P.; Pfau, M. Tetrahedron: Asymmetry 1994, 5,
1459.
(10) Of course, all compounds 6 have been prepared as racemic
materials on a larger scale and completely characterized. The
identity of the optically active compounds 6 has been
established on an analytical scale by 1H NMR spectroscopy
and gas chromatography.
(11) Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-199252 (5a), no. CCDC-199251 (6c)
and no. CCDC-199250 (8). Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or
e-mail: deposit@ccdc.cam.ac.uk].
(8) (S)-8-Methyl-2-oxaspiro[4.5]dec-7-ene-1,6-dione(6a). To
a solution of 5a (95.0 mg, 0.296 mmol) in H2O (15.0 mL) at
0 °C was added concd H2SO4 (2 drops), and after stirring for
1 h at 0 °C, the reaction mixture was allowed to warm up to
r.t. and extracted with EtOAc (3 × 50 mL). The combined
organic layers were dried (MgSO4), the solvent evaporated,
and the crude product purified by chromatography on SiO2
[petroleum ether–EtOAc, 1:2, Rf (MTB–cyclohexane,
5:1) 0.25] to give 6a as a colorless solid (30.0 mg, 0.166
(12) The nomenclature is, of course, dependent on constitution.
Configurations of structures in Scheme 2 are: (S)-5a, (S)-5b,
(R)-5c, (S)-6a, (S)-6b, and (S)-6c.
(13) Quantitative enantiomeric purity of 6a was established by
GLC on the chiral phase Bondex-un-α-5.6-Et-57.14
(14) For preparation of the chiral phase: Scherr, O. Dissertation;
Universität Stuttgart, 1997.
(15) Stefane, B.; Polanc, S. New J. Chem. 2002, 26, 28.
Synlett 2003, No. 4, 493–496 ISSN 0936-5214 © Thieme Stuttgart · New York