New chiral auxiliaries for the construction of quaternary stereocenters by copper-catalyzed Michael reactions

Article abstract of DOI:10.1002/1521-3773(20000804)39:15<2752::AID-ANIE2752>3.0.CO;2-5

The construction of quaternary stereocenters with 95-99% ee at ambient temperatures can be achieved by a copper-catalyzed Michael reaction with the application of α-amino acid amides as chiral auxiliaries [Eq. (1)]. These amides can be obtained in a few steps from the α-amino acids with standard transformations and, after the Michael reaction, they can be quantitatively recovered. Exclusion of water and oxygen is not necessary.

Full text of DOI:10.1002/1521-3773(20000804)39:15<2752::AID-ANIE2752>3.0.CO;2-5

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1,2-diaminocyclohexane.[8] We were able to prepare the
Michael product 6a in 91% ee at ambient temperature and
without exclusion of moisture. Similar results can only be
achieved with the LSB catalyst at À508C (93% ee).[9] Koga
and co-workers obtained ee values of 90% by using a chiral
auxiliary and a stoichiometric amount of a Brùnstedt base at
À1008C.[10] In this work we report on a new class of auxiliaries
for the transition metal catalyzed reaction of b-oxoesters 1
with simple enones, such as methyl vinyl ketone (MVK, 4),
and the synthesis of the Michael product 6a (Scheme 1) with
up to 99% ee at ambient temperature and without inert
conditions, a reaction which is unprecedented in the literature.
) A. Kuppermann in Potential Energy Surfaces and Dynamics
Calculations (Ed.: D. G. Truhlar), Plenum, New York, 1981, pp. 375.
[24] A. I. Boothroyd, W. J. Keogh, P. G. Martin, M. R. Peterson, J. Chem.
Phys. 1996, 104, 7139.
Ä
[25] F. J. Aoiz, L. Banares, V. J. Herrero in Advances in Classical Trajectory
Methods, Vol. 3 (Ed.: W. L. Hase), JAI, New York, 1998, pp. 121.
[26] F. J. Aoiz, L. BanÄares, V. J. Herrero, J. Chem. Soc. Faraday Trans. 1998,
94, 2483.
New Chiral Auxiliaries for the Construction of
Quaternary Stereocenters by Copper-Catalyzed
Michael Reactions**
Jens Christoffers* and Alexander Mann
The enantioselective construction of quaternary stereo-
centers is still a challenging goal in synthetic organic
chemistry.[1] Herein we report a new copper(ii)-catalyzed
and auxiliary-based Michael reaction which allows the con-
struction of quaternary carbon centers with ee values in excess
of 95% at ambient temperature (see Scheme 1). The Michael
À
reaction is an established method for C C bond formation
and is commonly catalyzed by a strong Brùnstedt base.[2] In
order to avoid the disadvantages of basic reaction conditions,
a number of transition metal catalyzed procedures has been
published in recent years; this has resulted in improved
chemoselectivity due to the milder reaction conditions.[3]
Moreover, chiral ligands can be utilized here to achieve
asymmetric catalysis of the Michael reaction. In the recent
years a number of chiral catalysts has been reported for the
conversion of 1,3-dicarbonyl compounds with a,b-unsaturated
ketones.[4] In particular, the introduction of the heterobime-
tallic lanthanum/sodium/[1,1'-binaphthyl]-2,2'-diol (LSB) cat-
alyst by Shibasaki and co-workers has to be mentioned here as
it defines the state of the art in this field.[5] However, the
reaction conditions are also Brùnstedt basic, and the enantio-
selective construction of quaternary stereocenters requires
low temperatures.
Scheme 1. Synthesis of 3a and the copper(ii)-catalyzed conversion with
MVK (4).
In the course of a combinatorial search,[11] we have
investigated a number of chiral amines 2a ± p derived from
a-amino acids which bear either a thioether, a tertiary amine,
or an amide group as an additional donor function.[12, 13] In an
Another strategy is the derivatization of the Michael donor
with a chiral amine as an auxiliary to give an imine or
enamine, which is subsequently converted with the Michael
acceptor.[6] If enamines derived from b-oxoesters are applied
according to this method, further activation, by addition of a
stoichiometric amount of Lewis acid or by high pressure and
low temperature, is required in order to achieve reasonable
yields and selectivity.[7] Recently we reported on the Ni-
catalyzed conversion of cyclic b-oxoesters in the presence of
acid-catalyzed reaction with the Michael donor 1a, these
amines yield the corresponding imines, which exist completely
as the tautomeric enamines 3a ± p; these enamines are
isolable, after chromatography, in good to excellent yields
(85 ± 95%).
[*] Dr. J. Christoffers, Dipl.-Chem. A. Mann
Technische Universität Berlin
In a primary screening the enaminoesters 3a ± p were each
converted in the presence of catalytic amounts of 14 different
metal salts 5a ± n[14] with MVK (4) in CH2Cl2. If a positive
effect was observed relative to the noncatalyzed reaction, with
regard to the selectivity of the formation of Michael product
6a, we started to optimize the reaction parameters. At this
first stage of the screening, we did not pay attention to the
Institut für Organische Chemie, Sekretariat C3
Strasse des 17. Juni 135, 10623 Berlin (Germany)
Fax : (‡49)30-723-12-33
E-mail: jchr@wap0105.chem.tu-berlin.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We are also grateful to the
Degussa-Hüls AG for gifts of amino acids and to Prof. Dr. S. Blechert
for his support.
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Table 1. Selected results for the screening of enaminoesters 3 with MVK (4) in the presence of different metal
salts 5.[a]
80 ± 90%. Without any catalyst
the yield is less than 15% after
12 ± 14 h. We were further in-
terested in whether our method
could be transferred to cyclic
Michael donors with different
ring sizes. As shown in Table 3,
the Michael product 6b can be
prepared with an ee value of
greater than 98% from the five-
membered ring b-oxoester 1b
attached to auxiliary 2g.[15] The
seven-membered ring com-
pound 1c can be converted into
Enamine
ee (6a) [%][b]
Metal salt (mol%)
ee (6a)[b]
Metal salt (mol%)
ee (6a)[b]
without metal salt
[%]
[%]
3c
3d
3e
3g
3h
3i
3l
3m
3o
28
Cu(OAc)2 ´ H2O (10)
2 ´ H2O (5)
59
57FeCl
73
86
76
86
20
37SnCl
23
SnCl2 (5)
43
59
50
68
77
73
50
35
21
47Cu(OAc)
(5)
3
53
78
72
66
33
29
20
Cu(OAc)2 ´ H2O (10)
Cu(OAc)2 ´ H2O (20)
Cu(OAc)2 ´ H2O (5)
Cu(OAc)2 ´ H2O (20)
Cu(OAc)2 ´ H2O (5)
NiCl2 (5)
FeCl3 (5)
Cu(OTf)2 (10)
FeCl3 (5)
FeCl3 ´ 6H2O (10)
SnCl2 (15)
2 (17.5)
[c]
Ni(OAc)2 ´ 4 H2O (5)
FeCl3 (5)
[a] Reaction conditions: Scale ˆ approximately 0.20 mmol of 3; 3:4 ˆ 1:2; solvent ˆ CH2Cl2. [b] The ee value of
6a was determined by GC on a chiral phase.[15] The yields were not determined. [c] Tf ˆ F3CSO2.
yield. Selected results are given in Table 1. Auxiliaries derived
Table 3. Variation of the Michael donor 1 in acetone.
from valine and iso- or tert-leucine with an additional amide
function (2a ± i), when attached to the Michael donor,
induced selectivities up to 78% ee even without any metal
salt. In every case the R isomer was found to be the major
enantiomer.[8] When Cu(OAc)2 ´ H2O was applied as the
catalyst, the ee values were clearly improved by about 20%.
Auxiliaries with a thioether or tertiary amino function did not
show promising results and, for this reason, were not
considered for further optimizations.
Improvement in selectivity was also achieved by variation
of the solvent: With acetone as the solvent the enantioselec-
tivity for the copper(ii) catalysis was dramatically raised.
Greater than 95% ee values were obtained with the enam-
inoesters 3a, c, d, f, g, and i (Table 2). In particular, when
Michael
donor
Auxiliary
Catalyst
[mol%]
Product
ee
[%]
Yield
[%]
1b
1c
2g
2g
5
10
6b[a]
6c
ꢀ 98
40
84
74[b]
[a] R enantiomer.[8] [b] The ee of 6c was determined after derivatization to
7b.[15]
product 6c in 74% ee by use of the same auxiliary 2g (ee value
determined after derivatization to compound 7b).[15]
Table 2. Asymmetric Michael reactions of enaminoesters 3 with MVK (4)
in the presence of Cu(OAc)2 ´ H2O (5a) in acetone.[a]
Enamine
ee (6a) [%][b]
amount of 5a [mol%]
0
2.5
5
10
20
3a
3b
3c
3d
3 f
3g
3i
5798
65
55
55
76
85
7
98
98
84
95
9798
97
96
98
85
94
83
85
92
93
95
93
96
92
90
9799
92
93
Regarding the mechanism of the reaction we can only
91
0
91
92
speculate at the moment. However, we suppose that this Cu-
catalyzed variant of an auxiliary-mediated Michael reaction
does not proceed via a cyclic transition state as proposed by
dꢁAngelo and co-workers,[6] but instead through an inter-
mediate 8, in which the enamine 3 coordinates as a tridentate
ligand to the copper center and, thereby, effects a diastereo-
facial differentiation. At the same time the enone is activated
by coordination to the metal center.[8]
The copper-catalyzed auxiliary-mediated Michael reaction
of cyclic b-oxoesters with MVK introduced herein allows, for
the first time, the construction of quaternary stereocenters in
80 ± 90% yield with up to 99% ee. The reaction proceeds at
ambient temperature and under mild conditions. Exclusion of
air or moisture is not necessary. As chiral auxiliaries a-amino
acid amides, which are readily available by standard trans-
formations from a-amino acids, are applied; they are almost
quantitatively recoverable after the reaction.
[a] Reaction conditions: Scale ˆ approximately 0.20 mmol of 3; 3:4 ˆ 1:2;
solvent ˆ acetone. [b] For enantioselectivities of greater than 95% the ee
values were additionally checked after derivatization to 7a.[15]
compounds 3a and 3d were used with 2.5 or 10 mol% of
catalyst, selectivities of up to 98% ee were achieved. An
increase to 99% ee resulted when compound 3g was used in
the presence of 20 mol% Cu(OAc)2 ´ H2O. With these results,
the protocol presented here is the most selective method
known so far for the stereoselective generation of quaternary
carbon centers by Michael reactions of b-oxoesters with
MVK. However, only the auxiliaries derived from valine and
iso- or tert-leucine show such high selectivities. The yields are
dependent upon the reaction time and the amount of catalyst
applied. The use of 2.5 mol% of catalyst gives 65 ± 75% yield
after 12 ± 14 h. If more catalyst is employed, the yields rise to
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[11] a) J. Christoffers, A. Mann, J. Pickardt, Tetrahedron 1999, 55, 5377 ±
5388; b) J. Christoffers, A. Mann, Eur. J. Org. Chem. 1999, 1475 ± 1479;
c) J. Christoffers, J. Prakt. Chem. 1999, 341, 495 ± 498; d) J. Christof-
fers, U. Röûler, Tetrahedron: Asymmetry 1999, 10, 1207± 1215.
[12] Syntheses of auxiliaries 2a ± j were accomplished in three steps from
the appropriate a-amino acids: a) Boc2O, DMAP (3 mol%), H2O/
MeOH 1/1, 70 ± 80%; b) DCC, HNR2', CH2Cl2, 65 ± 85%;
Experimental Section
3g (representative procedure): A mixture of (S)-tert-leucine dimethyl-
amide (2g; 696 mg, 4.40 mmol), oxoester 1a (749 mg, 4.40 mmol), and
molecular sieves (4 Š, 2.5 g) in toluene (6 mL) under nitrogen was treated
with a catalytic amount of concentrated HCl. After stirring for 14 h at 608C,
the reaction mixture was filtered and the residue washed with CH2Cl2. All
volatile materials were removed in vacuo and the residue was chromato-
graphed on Al2O3 90 (Activity II ± III; eluent ˆ methyl tert-butylether/
petroleum ether 3/1; Rf ˆ 0.45) to yield 3g as a colorless solid (1.17g,
3.78 mmol, 86%). m.p. 1048C; [a]2D0 ˆ ‡194 (c ˆ 5.8, CHCl3); 1H NMR
(400 MHz, CDCl3): d ˆ 1.05 (s, 9H), 1.25 (t, J ˆ 7.1 Hz, 3H), 1.47 ± 1.58 (m,
2H), 1.58 ± 1.67(m, 2H), 1.99 ± 2.09 (m, 1H), 2.22 ± 2.34 (m, 3H), 2.97(s,
3H), 3.11 (s, 3H), 4.09 ± 4.20 (m, 2H), 4.24 (d, J ˆ 9.9 Hz, 1H), 9.45 (d, J ˆ
9.8 Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3): d ˆ 14.61 (CH3), 22.43
(CH2), 22.55 (CH2), 23.97(CH 2), 26.66 (CH3), 26.76 (CH2), 35.74 (CH3),
c) CF3CO2H,
CH2Cl2,
90 ± 99%.
Boc ˆ tert-butoxycarbonyl,
DMAP ˆ 4-dimethylaminopyridine,
DCC ˆ dicyclohexylcarbodi-
imide.
[13] Syntheses of auxiliaries 2m ± p were accomplished in four steps from
the appropriate amino alcohols: a) Boc2O, CH2Cl2, quantitative;
b) TosCl, pyridine, 65 ± 90%; c) for 2m, n: NaSEt, DMF, 90 ± 95%;
for 2o, p: HNMe2, pyridine, 75 ± 95%; d) CF3CO2H, CH2Cl2, 90 ±
99%. Tos ˆ p-H3CC6H4SO2.
[14] Applied metal salts: Cu(OAc)2 ´ H2O (5a), Cu(OTf)2 (5b), FeCl3 (5c),
FeCl3 ´ 6 H2O (5d), NiCl2 (5e), Ni(OAc)2 ´ 4H2O (5 f), SnCl2 (5g),
AgOAc (5h), CoCl2 ´ 6H2O (5i), CrCl3 ´ 6H2O (5j), MgBr2 (5k),
Pb(OAc)2 ´ 3H2O (5l), ZnBr2 (5m), ZnCl2 (5n). Tf ˆ F3CSO2.
[15] Details about GC analysis and derivatization procedures have
recently been reported by us.[8]
35.96 (C), 37.90 (CH ), 57.75 (CH), 58.72 (CH2), 91.27(C), 156.47(C),
3
ˆ
ˆ
170.41 (C O), 171.67 (C O); HR MS (EI, 70 eV): calcd: 310.2256, found:
310.2249; elemental analysis (%): calcd for C17H30N2O3 (310.44): C 65.77, H
9.74, N 9.02; found: C 65.94, H 9.76, N 9.16.
Copper(ii)-catalyzed Michael reaction of 3a (representative procedure):
Enaminoester 3a (0.216 mmol, 70.1 mg) and Cu(OAc)2 ´ H2O (5a;
0.0054 mmol, 1.1 mg) were stirred in acetone (1 mL) at 238C for 1 h.
MVK (4; 0.43 mmol, 30 mg) was added and the mixture was stirred for
additional 12 ± 14 h at 238C. All volatile materials were removed in vacuo
and the residue was treated with 2 n HCl. The mixture was stirred
vigorously for 4 ± 5 h and subsequently extracted with methyl tert-butyl-
ether.[16] After washing (saturated aqueous NaHCO3) und drying (MgSO4)
of the combined extracts, the solvent was evaporated and the residue was
chromatographed on SiO2 (methyl tert-butylether/petroleum ether 1/2,
Rf ˆ 0.19). Compound 6a (0.186 mmol, 44.6 mg, 86%) was obtained as a
colorless oil. The ee value of 98% was determined by GC with a chiral
column after derivatization to compound 7a.[15]
[16] Auxiliary 2 can be almost quantitatively recovered from the aqueous
layer after basic workup.
Detection of a 2,3-Aminomutase in the
Mushroom Cortinarius violaceus**
Received: February 25, 2000 [Z14769]
Peter Spiteller, Matthias Rüth, Franz von Nussbaum,
and Wolfgang Steglich*
[1] Reviews: a) E. J. Corey, A. Guzman-Perez, Angew. Chem. 1998, 110,
402 ± 415; Angew. Chem. Int. Ed. 1998, 37, 388 ± 401; b) K. Fuji, Chem.
Rev. 1993, 93, 2037± 2066.
[2] Reviews: a) E. D. Bergmann, D. Ginsburg, R. Pappo, Org. React.
1959, 10, 179 ± 555; b) D. A. Oare, C. H. Heathcock in Topics in
Stereochemistry, Vol. 19 (Eds.: E. L. Eliel, S. H. Wilen), Wiley
Interscience, New York, 1989, pp. 227± 407; c) P. Perlmutter, Con-
jugate Addition Reactions in Organic Synthesis, Tetrahedron Organic
Chemistry Series Vol. 9, Pergamon, Oxford, 1992.
[3] a) J. Christoffers, J. Chem. Soc. Perkin Trans. 1 1997, 3141 ± 3149;
b) review: J. Christoffers, Eur. J. Org. Chem. 1998, 1259 ± 1266.
[4] a) H. Brunner, B. Hammer, Angew. Chem. 1984, 96, 305 ± 306; Angew.
Chem. Int. Ed. Eng. 1984, 23, 312 ± 313; b) G. Desimoni, G. Dusi, G.
Faita, P. Quadrelli, P. Righetti, Tetrahedron 1995, 51, 4131 ± 4144; c) N.
End, L. Macko, M. Zehnder, A. Pfaltz, Chem. Eur. J. 1998, 4, 818 ± 824.
[5] a) H. Sasai, T. Arai, Y. Satow, K. N. Houk, M. Shibasaki, J. Am. Chem.
Soc. 1995, 117, 6194 ± 6198; b) review: M. Shibasaki, H. Sasai, T. Arai,
Angew. Chem. 1997, 109, 1290 ± 1310; Angew. Chem. Int. Ed. Eng.
1997, 36, 1236 ± 1256.
[6] a) M. Pfau, G. Revial, A. Guingant, J. dꢁAngelo, J. Am. Chem. Soc.
1985, 107, 273 ± 274; reviews: b) J. dꢁAngelo, D. DesmaeÈle, F. Dumas,
A. Guingant, Tetrahedron: Asymmetry 1992, 3, 459 ± 505; c) J.
Leonard, E. Díez-Barra, S. Merino, Eur. J. Org. Chem. 1998, 2051 ±
2061.
Recently, we discovered the new natural b-amino acid (R)-
3,4-dihydroxy-b-phenylalanine ((R)-b-dopa, (R)-3) in the
mushroom Cortinarius violaceus.[1] (R)-3 is present in the
mushroom as the iron(iii) ± catechol complex, which gives the
fruit bodies their blue-purple color.
In this communication we report on the biosynthesis of (R)-
b-dopa. For this purpose, suitable precursors were applied to
young fruit bodies of C. violaceus, which were then harvested
5 to 7days later. All mushrooms showed normal growth and
became double their original size. After extraction of the fruit
bodies with methanol, the amino acids were isolated by ion
exchange chromatography and further investigated by GC/
MS as their trimethylsilyl derivatives. The incorporation of
13C-labeled precursors was determined by NMR spectroscopy.
After feeding with rac-3-fluorotyrosine, we were able to
detect the formation of 5-fluoro-b-dopa as well as traces of
3-fluoro-b-tyrosine (Table 1, entry 1).[2] This proves that
tyrosine (1) is the biosynthetic precursor of b-dopa (3). This
result is confirmed by the successful conversion of rac-[3'-
[7] A. Guingant, H. Hammami, Tetrahedron: Asymmetry 1991, 2, 411 ±
414.
[8] J. Christoffers, U. Röûler, T. Werner, Eur. J. Org. Chem. 2000, 701 ±
705.
[9] H. Sasai, E. Emori, T. Arai, M. Shibasaki, Tetrahedron Lett. 1996, 37,
5561 ± 5564.
[10] a) K. Tomioka, W. Seo, K. Ando, K. Koga, Tetrahedron Lett. 1987, 28,
6637± 6640; b) K. Ando, W. Seo, K. Tomioka, K. Koga, Tetrahedron
1994, 50, 13081 ± 13088.
[*] Prof. Dr. W. Steglich, Dipl.-Chem P. Spiteller, Dipl.-Chem. M. Rüth,
Dr. F. von Nussbaum
Department Chemie der Ludwig-Maximilians-Universität
Butenandtstrasse 5 ± 13, Haus F, 81377 München (Germany)
Fax : (‡49)89-2180-7756
E-mail: wos@cup.uni-muenchen.de
[**] This contribution was supported by the Deutsche Forschungsgemein-
schaft (SFB 369).
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Angew. Chem. Int. Ed. 2000, 39, No. 15