Preparation and asymmetric hydrogenation of β-aryl-substituted β-acylaminoacrylates

Article abstract of DOI:10.1002/anie.200390242

The Rh-catalyzed asymmetric hydrogenation of β-aryl-substituted (E)-β-acylaminoacrylates, which were isolated for the first time, with, for example [Rh{(R,R)- (Et-FerroTANE)}(nbd)]⁺ as catalyst (see picture) proceeds under very mild conditions

Full text of DOI:10.1002/anie.200390242

Angewandte
Chemie
Heinzmann population analysis based on occupation numbers.
The SENs for bonds are a reliable measure of the covalent
Experimental Section
Liquid germanium was treated with HBr under high vacuum at
15508C, and the resulting gaseous products were condensed into a
toluene/NnPr3 (5:1) mixture at À1968C. After the cocondensate was
allowed to warm up to À788C, a dark red emulsion, consisting of a
dark red oil in a pale yellow solution, was obtained. The emulsion was
then treated with Na[N-
À
bonding strength. For example, the SEN for the Ge Ge single
À
bond in the model compound R3Ge GeR3 (R = NH2) is 1.04.
Turbomole: O. Treutler, R. Ahlrichs, J. Chem. Phys. 1995, 102,
346; BP-86-functional: J. P. Perdew, Phys. Rev. B 1986, 33, 8822;
A. D. Becke, Phys. Rev. A 1988, 38, 3098; RI-DFT: K. Eichkorn,
O. Treutler, H. Öhm, M. Häser, R. Ahlrichs, Chem. Phys. Lett.
1995, 240, 283; SVP: A. Schäfer, H. Horn, R. Ahlrichs, J. Chem.
Phys. 1992, 97, 2571; Ahlrichs–Heinzmann population analysis:
E. R. Davidson, J. Chem. Phys. 1967, 46, 3320; K. R. Roby, Mol.
Phys. 1974, 27, 81; R. Heinzmann, R. Ahlrichs, Theor. Chim.
Acta 1976, 42, 33; C. Erhardt, R. Ahlrichs, Theor. Chim. Acta
1985, 68, 231.
(SiMe3)2] in toluene at À788Cand was slowly allowed to warm to
room temperature, resulting in a nearly black reaction mixture.
Removal of the solvent under vacuum yielded a black oil, which,
when extracted with toluene, gave a black toluene extract and a white
residue (NaBr). Over several weeks, dark red crystals of [Ge8{N-
(SiMe3)2}6] (50 mg, 0.032 mmol) formed in the black toluene extract.
Crystal structure data for 1: Mr = 1727.35 gmolÀ1, crystal dimen-
sions 0.5 ” 0.4 ” 0.2 mm, triclinic, space group P1, a = 12.595(3), b =
12.768(3), c = 13.223(3) Š, a = 95.92(3), b = 103.53(3), g = 91.53(3)8,
V= 2053.4(7) Š3, Z = 1, 1calcd = 1.397 gcmÀ3
2qmax = 64.488, 51019 measured, 14354 independent reflections
(R(int.) = 0.0366), absorption correction numerical (min./max. trans-
mission 0.3683/0.5333), R1 = 0.0320, wR2 = 0.0821. Stoe-IPDS(II)
diffractometer (MoKa radiation, l = 0.71073 Š, 200 K). The structure
was solved by direct methods and refined against F2 for all observed
reflections. Programs used: Shelxs and Shelxl (G. M. Sheldrick,
Universität Göttingen). CCDC-192664 contains the supplementary
crystallographic data for this paper. These data can be obtained
online free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ; Fax: (+ 44)1223-336-033; or deposit@ccdc.
cam.ac.uk).
ꢀ
[13] Compound 1 could thus be formally described as a triplet
diradical; however, EPR measurements of 1 show no signal. This
seems logical in light of the results of the quantum-chemical
calculations, which calculate a singlet state as the ground state
for all of the model compounds. Thus 1 can be formally
described as a diradical in the singlet state, which invites
comparison with the 1.1.1-propellanes[16] and diradicaloids.[17]
While the distance between radical centers in the 1.1.1-propel-
,
mMo = 3.094 mmÀ1
,
À
lanes is about 300 pm, the Ge Ge distance in 1 of 518 pm is
À
substantially larger, which makes a direct Ge Ge interaction
questionable. On the other hand, the energy difference of
96.5 kJmolÀ1 between the singlet and triplet states is of the same
order of magnitude as those of the 1.1.1-propellanes.
[14] A. Schnepf, H. Schnöckel, Angew. Chem. 2001, 113, 734; Angew.
Chem. Int. Ed. 2001, 40, 711.
[15] J. Hagel, M. T. Kelemen, G. Fischer, B. Pilawa, J. Wosnitza, E.
Dormann, H. von Löhneysen, A. Schnepf, H. Schnöckel, U.
Neisel, J. Beck, J. Low Temp. Phys. 2002, 129, 133.
[16] M. S. Gordon, K. A. Nguyen, M. T. Carroll, Polyhedron 1991, 10,
1247.
Received: September 6, 2002 [Z50117]
[1] J. D. Corbett, Angew. Chem. 2000, 112, 682; Angew. Chem. Int.
Ed. 2000, 39, 671.
[2] N. Wiberg, W. Hochmuth, H. Nöth, A. Appel, M. Schmidt-
Amelunxen, Angew. Chem. 1996, 108, 1437; Angew. Chem. Int.
Ed. Engl. 1996, 35, 1333.
[17] H. Grützmacher, F. Breher, Angew. Chem. 2002, 114, 4178;
Angew. Chem. Int. Ed. 2002, 41, 4006.
[3] a) A. Sekigushi, C. Kabuto, H. Sakurai, Angew. Chem. 1989, 101,
97; Angew. Chem. Int. Ed. Engl. 1989, 28, 55; b) A. Sekigushi, T.
Yatabe, S. Doi, H. Sakurai, Phosphorus Sulfur Silicon Relat.
Elem. 1994, 93, 193.
[4] a) A. Sekigushi, T. Yatabe, H. Kamatani, C. Kabuto, H. Sakurai,
J. Am. Chem. Soc. 1992, 114, 6260; b) M. Unno, K. Higuchi, K.
Furuya, H. Shioyama, S. Kyushin, M. Goto, H. Matsumoto, Bull.
Chem. Soc. Jpn. 2000, 73, 2093.
[5] A. Sekiguchi, H. Sakurai, Adv. Organomet. Chem. 1995, 37, 1.
[6] A. Sekiguchi, H. Naito, H. Nameki, K. Ebata, C. Kabuto, H.
Sakurai, J. Organomet. Chem. 1989, 368, C 1.
[7] M. Weidenbruch, F.-T. Grimm, S. Pohl, W. Saak, Angew. Chem.
1989, 101, 201; Angew. Chem. Int. Ed. Engl. 1989, 28, 198.
[8] a) L. R. Sita, R. D. Bickerstaff, J. Am. Chem. Soc. 1989, 111,
6454; b) N. Wiberg, H.-W. Lerner, S. Wagner, H. Nöth, T. Seifert,
Z. Naturforsch. B 1999, 877; c) B. E. Eichler, P. P. Power, Angew.
Chem. 2001, 113, 818; Angew. Chem. Int. Ed. 2001, 40, 796;
d) L. R. Sita, Acc. Chem. Res. 1994, 27, 191.
[9] C. Dohmeier, D. Loos, H. Schnöckel, Angew. Chem. 1996, 108,
141; Angew. Chem. Int. Ed. Engl. 1996, 35, 129; A. Schnepf, H.
Schnöckel, Angew. Chem. 2002, 114, 3682; Angew. Chem. Int.
Ed. 2002, 41, 3532.
[10] CRC Handbook of Chemistry and Physics, 76th ed, (Ed.: D. R.
Lide), CRC, New York, 1995, 4-95.
[11] A. Schnepf, R. Köppe, Z. Anorg. Allg. Chem. 2002, 628, 2914.
[12] Quantum-chemical calculations were carried out with the RI-
DFT version of the Turbomole program package, by employing
the Becke–Perdew 86-functional. The basis sets were of SVP
quality. The electronic structure was analyzed with the Ahlrichs–
Asymmetric Hydrogenation
Preparation and Asymmetric Hydrogenation of
b-Aryl-Substituted b-Acylaminoacrylates**
Jingsong You, Hans-Joachim Drexler, Songlin Zhang,
Christine Fischer, and Detlef Heller*
The synthetic opportunities for the preparation of optically
active b-amino acids are based mainly on stoichiometric
reactions with chiral auxiliaries and to a significantly lesser
[*] Priv.-Doz. Dr. D. Heller, Dr. J. You, Dr. H.-J. Drexler, Dr. S. Zhang,
Dr. C. Fischer
Institut für Organische Katalyseforschung
an der Universität Rostock e.V.
Buchbinderstrasse 5/6, 18055 Rostock (Germany)
Fax: (+49)381-466-9383
E-mail: detlef.heller@ifok.uni-rostock.de
[**] We thank the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie for the generous support of this work. We are
grateful to Dr. R. McCague and Dr. A. Zanotti-Gerosa of ChiroTech
for catalysts and ligands.
Supporting information for this article is available on the WWW
under http://www.angewandte.de or from the author.
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Communications
extent on stereoselective catalytic reactions.[1] Within this
context the asymmetric hydrogenation of the respective b-
dehydroamino acid precursors with chiral Rh or Ru catalysts
is one of the most promising methods.[2] The required
prochiral substrates are accessible by the reaction of b-
ketocarboxylates with NH4OAc and subsequent acyla-
tion.[2g,h] In this way E/Z mixtures are formed (Scheme 1),
which in the case of b-alkyl-substituted b-acylaminoacrylates
Scheme 1. Products of the reaction of b-ketocarboxylates with NH4OAc
and subsequentacylation.
(R2 = alkyl) are readily separated and can be hydrogenated
with high enantiomeric selectivity under mild conditions. The
trend that in hydrogenation reactions the E isomers lead to
higher—and also hydrogen pressure independent—enantio-
selectivities than the Z isomers appears characteristic,[2e,g] but
see also reference [2b]. In contrast both isomer separation and
asymmetric hydrogenation of the corresponding b-aryl-sub-
stituted b-acylaminoacrylates (R2 = aryl) is problematic. Thus
far the reduction of such substrates with sufficiently high
enantioselectivities by Rh catalysis has not been successful.
Recently Zhang et al. successfully hydrogenated a broad
spectrum of b-aryl-substituted b-acetylaminoacrylates[2c] with
Ru catalysts with binapo derivatives[13] as ligands. At 508C
and a hydrogen pressure of 5 bar enantiomeric excesses of up
to 99% could be achieved. However, the substrate/catalyst
ratio is only 25:1, and the reaction time is 20 h. Since the E/Z
mixtures clearly cannot be separated—E/Z ratios of 5:95 to
40:60 have been described for the different b-aryl substituted
compounds—the possibility of hydrogenation of substrate
mixtures is an advantage.
The aim of the present work was to investigate E isomers
of b-aryl-substituted b-acylaminoacrylates in Rh-catalyzed
asymmetric hydrogenation. During the preparation of methyl
3-acetylamino-3-phenylacrylate by the usual method a pre-
viously undescribed spot was found in the thin layer
chromatogram in addition to the starting material, the C-
acetylated compound, and the Z isomer together with the
compound universally recognized in the literature[2c,g,h] as the
“E isomer”. After isolation by column chromatography its
analysis showed surprisingly that this compound is the E
isomer of methyl 3-acetylamino-3-phenylacrylate![3]
Figure 1. Crystal structure of methyl 3-diacetylamino-3-phenylacrylate
(ellipsoids set at the 50% probability level).
carried out at lower temperatures with less acylating agent
(suppression of the formation of the N,N-diacylated product)
the total amount of E isomer may be significantly increased.
There is also the additional benefit that because of its poor
solubility the E isomer usually crystallizes out on removal of
the solvent (see Supporting Information).
Whereas classical ligands such as dipamp[13] or diop[13]
induce only modest enantioselectivities, Rh catalysts of the
DuPHOS type[13] lead to good ee values for the hydrogenation
of b-alkyl-substituted substrates. Et-FerrroTANE[13] produces
still further improvements for the E isomer substrates, with
enantioselectivities of ꢀ 99% ee (Table 1). Thus the overall
trend that E isomer substrates lead to higher enantioselectiv-
ities than the corresponding Z-isomers is confirmed. This
difference is particularly large with the use of Et-FerroTANE
as ligand, although the causes for this are not clear.
One advantage of the catalyst with Et-FerroTANE as
ligand is that in contrast to DuPHOS derivatives the E
Table 1: Enantioselectivities of the hydrogenation of different E and Z
isomers of b-alkyl-substituted b-acylaminoacrylates with [Rh(ligand)-
(MeOH)2]BF4 as catalyst.[7] [a]
%ee for
Z isomer
%ee for
E isomer
Ligand
For its characterization the compound originally called
the “E isomer” was next isolated.[4] Comprehensive analysis
(see Supporting Information) shows unambiguously that the
compound erroneously described in the literature as the “E
isomer” is actually the N,N-diacetylated product. Figure 1
shows the crystal structure of this compound.[5]
The reason for the poor E/Z ratios in the usual synthesis of
b-aryl-substituted b-acylaminoacrylates[2g,h] is evidently the
heating under reflux during the acylation of the amine. As a
result increased isomerization of the E to the thermodynami-
cally more stable Z compound occurs.[6] If the acylation is
R1
R2
R3
diop[8a]
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
iPr
Me
Me
Me
Ph
Me
Ph
17
68
87
85
28
32
31
71
90
98
96
99
dipamp[8b]
Et-DuPHOS[8c,d]
Me-DuPHOS[8c,d]
Et-FerroTANE[8e,f]
Et-FerroTANE
Et-FerroTANE
>99
>99
Me
[a] Standard conditions: 0.005 mmol catalyst, 0.5 mmol substrate,
7.5 mL MeOH, 1.0 bar total pressure, 258C, in each case 100%
conversion.
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Chemie
isomers are more rapidly hydrogenated than the Z isomers.
The exceptional selectivity and activity of the Rh catalyst with
the commercially available ligand Et-FerroTANE is also
confirmed by the hydrogenation of b-aryl- substituted sub-
strates (Table 2).[9]
Table 2: Enantioselectivities for the hydrogenation of b-aryl-substituted
(E)-b-acetylaminoacrylates with [Rh{(R,R)-(Et-FerroTANE)}(MeOH)2]BF4
as catalyst.[a]
Enantiomeric
excesses [%ee]
R2
R1
phenyl
phenyl
Me
Et99 (
Me
Et
Me
Me
Me
Et
>99 (S)[10]
S)
>99 (S)
99 (S)
98 (S)
98 (S)
>99 (S)
>99 (S)
98 (S)
p-methylphenyl
p-methylphenyl
p-methoxyphenyl
p-chlorophenyl
p-fluorophenyl
p-fluorophenyl
o-methoxyphenyl
m-nitrophenyl
Figure 2. Crystal structure of the cation in [Rh{(R,R)-(Et-Ferro-
TANE)}(nbd)]BF4 (ellipsoids set at the 30% probability level, only the
H atoms at the asymmetric C atoms are shown). Selected bond
lengths [Š] and angle [8]: Rh1-P1 2.322(2), Rh1-P2 2.306(2); P1-Rh1-P2
98.27(5). The best planes for the four atoms of the two phosphetane
rings intersect at an angle of 41.88 (mean deviation of the atoms
0.1328 and 0.1421 Š, respectively).
Me
Et
99 (S)
[a] Standard conditions: 0.005 mmol catalyst, 0.5 mmol substrate,
7.5 mL MeOH, 1.0 bar total pressure, 258C, in each case 100%
conversion.
Table 3: P-Rh-P angles (bite angles) for different RhI complexes
determined by X-ray structure analysis.
With the exception of the p-methoxyphenyl-substituted
substrate the enantioselectivities achieved are the same or
better than those recently described by Zhang et al.[2c] It is
noteworthy that in the case of Rh catalysis a higher
enantiomeric excess is also obtained for the substrate with
the o-methoxyphenyl moiety (Ru catalysis: 80% ee for the
corresponding “E”/Z substrate mixture[2c]).
The high activity under the selected standard reaction
conditions of 0.005 mol catalyst (0.666 mmolLÀ1) and
0.5 mmol substrate must also to be stressed. All the substrates
listed in Table 2 react in pseudo-first-order reactions, the half
lifetimes lie between about 0.5 (aryl = phenyl) and about
1.8 min (aryl = m-nitrophenyl). Owing to the high activity the
substrate/catalyst ratio can be increased to 1000 with com-
plete conversion in the case of, for example, methyl (E)-3-
acetylamino-3-phenylacrylate.
Complex
Bite angle [8]
Reference
[Rh(Me-DuPHOS)(cod)]SbF6
[Rh(Me-DuPHOS)(nbd)]BF4
[Rh(Me-DuPHOS)(toluene)]BF4
[Rh(Et-DuPHOS)(cod)]BARF
[Rh(Et-DuPHOS)(nbd)]BF4
[Rh(Et-DuPHOS)(cod)]BF4
[Rh(Et-DuPHOS)(benzene)]BF4
[Rh(Et-FerroTANE)(nbd)]BF4
84.7
84.6
84.9
85.4
84.5/84.7
85.3
84.5
[8d]
this work
[2d]
[12]
[7a]
[7a]
[2d]
this work
98.3
bite angle it is also noteworthy that the phosphetane rings are
highly tilted relative to each other at an angle of about 428. In
the case of phospholane rings the analogous angle is only
about 88. The example of Et-FerroTANE also shows that very
high enantioselectivities and activities are achievable in
asymmetric hydrogenation with ligands that have a very
flexible backbone (ferrocene unit) and that lead to a large bite
angle in the complex.
The reasons for the high activities and selectivities with
the use of Et-FerroTANE as ligand are unclear, noticeable is
however the large P-Rh-P angle (bite angle)[11] of 98.38 for the
[13]
complex [Rh{(R,R)-(Et-FerroTANE)}(nbd)]BF4
(Table 3
and Figure 2; further data on the X-ray structure analysis of
this complex—to our knowledge the first structural confir-
mation for an Rh complex with a chelating cis-bonded ligand
which contains phosphetanes—and the complex [Rh{(S,S)-
(Me-DuPHOS)}(nbd)]BF4 may be found in the Supporting
Information).
In contrast, an average bite angle of 84.8 Æ 0.58 is found
for seven DuPHOS derivatives of known structure. This is
clearly independent of the anion, different h4-bonded di-
olefins or h6-bonded arenes, and also independent of the
substitution on the phospholane ring. In addition to the large
Thus we have succeeded for the first time to prepare b-
aryl-substituted (E)-b-acylaminoacrylates and to show that in
the case of methyl 3-acetylamino-3-phenyl acrylate the
compound originally considered erroneously to be the “E
isomer” is the N,N-diacetylated product. By lowering the
temperature during acylation and with smaller amounts of
acylation agents the fraction of E isomer may be increased
significantly. The Rh-catalyzed, asymmetric hydrogenation of
further novel b-aryl-substituted (E)-b-acylaminoacrylates
with the commercially available Et-FerroTANE as chiral
ligand leads under very mild conditions (258C, normal
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[9] The hydrogenation of the corresponding Z isomers with the Et-
FerroTANE system leads, as expected, to enantioselectivities of
only 25–80% ee. Orienting investigations with Me-DuPHOS
with the E isomers as substrates gave throughout poorer
enantioselectivities and activities.
pressure) and high substrate/catalyst ratios to very good
enantioselectivities.
Received: September 30, 2002 [Z50265]
[10] In the case of the p-chlorophenyl-substituted product the
determination of the absolute S configuration was achieved by
X-ray structure analysis (see Supporting Information). Since all
other hydrogenation products also gave negative rotations they
should equally be S-configurated, which is in agreement with
literature data.
[11] P. Dierkes, P. W. N. M. van Leeuwen, J. Chem. Soc. Dalton Trans.
1999, 1519 – 1529.
[12] B. Guzel, M. A. Omary, J. P. Fackler, A. Akgerman, Inorg. Chim.
Acta 2001, 325, 45 – 50.
[13] Abreviations used: binapo = 2,2’-Bis(diphenylphosphanyl)-1,1’-
binaphthyl, dipamp = 1,2-ethanediylbis[(2-methoxyphenyl)phe-
nylphosphane], diop = 2,3-O-isopropylidene-2,3-dihydroxy-1,4-
bis(diphenylphosphanyl)butane, Me-DuPHOS = 1,2-bis(2,5-di-
methylphospholanyl)benzene, Et-FerroTANE = 1,1’-bis(2,4-di-
ethylphosphetanyl)ferrocene, nbd = 3,5-norbornadiene, cod =
1,5-cyclooctadiene.
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Synthesis of Lipoteichoic Acids
[4] The hydrogenation of an “E”/Z mixture under normal pressure
at room temperature in MeOH with [Rh(Me-DuPHO-
S)(cod)]BF4[13] leads to the hydrogenation of the Z isomer only,
the “E isomer” remains unchanged. Unlike the starting materi-
als, which are difficult to separate, the hydrogenation product is
readily separated from the unchanged “E isomer” by column
chromatography when the latter is obtained in a pure state.
Synthesis of the First Fully Active Lipoteichoic
Acid**
Andreas Stadelmaier, Siegfried Morath,
Thomas Hartung, and Richard R. Schmidt*
[5] CCDC-194044
(methyl(E)-3-acetylamino-3-phenylacrylate),
CCDC-194047 (methyl 3-diacetylamino-3-phenylacrylate),
Dedicated to Professor Ewald Daltrozzo
on the occasion of his 65th birthday
CCDC-194046 (methyl(S)-3-acetylamino-3-p-chlorophenylpro-
pionate),
CCDC-194045
([Rh{(R,R)-(Et-FerroTA-
NE)}(nbd)]BF4), and CCDC-194043 ([Rh{(S,S)-(Me-Du-
PHOS)}(nbd)]BF4) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
The inflammatory response to Gram-negative and Gram-
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most of the responses to Gram-negative bacteria could be
attributed to lipopolysaccharides (LPS) and their lipid anchor
lipid A, as general principles,[1–3] no corresponding priniciple
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[*] Prof. Dr. R. R. Schmidt, A. Stadelmaier
Fachbereich Chemie
Universität Konstanz, Fach M 725
78457 Konstanz (Germany)
Fax: (+49)7531-883-135
E-mail: richard.schmidt@uni-konstanz.de
Dr. S. Morath, Dr. T. Hartung
Fachbereich Biologie
Universität Konstanz
78457 Konstanz (Germany)
[**] This work was supported by the Deutsche Forschungsgemeinschaft
and the Fonds der Chemischen Industrie. We thank S. Deininger
and J. Kley for technical assistance, L. Cobianchi for help in
separating the final products by HI-chromatography, and Prof. Dr.
A. Geyer and A. Friemel for help in the structural assignments of the
final products by NMR experiments.
916
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1433-7851/03/4208-0916 $ 20.00+.50/0
Angew. Chem. Int. Ed. 2003, 42, No. 8