Synthesis of a new chiral bisphospholane ligand for the Rh(I)-catalyzed enantioselective hydrogenation of isomeric β-acylamido acrylates

Article abstract of DOI:10.1021/jo020453h

The highly stereoselective synthesis of a chiral silylphospholane has been described, which can be advantageously used as a building block under base-free conditions for the construction of diphosphines related to DuPHOS. The utility of silylphospholane is shown in the synthesis of a new bisphospholane ligand 1 (MalPHOS), which is characterized by a maleic anhydride backbone. The ligand forms with Rh(I) a complex with a larger bite angle P-Rh-P than the analogue Me-DuPHOS complex. Both complexes have been tested in the asymmetric hydrogenation of unsaturated α- and β-amino acid precursors of pharmaceutical relevance. In several cases, the new catalyst was superior in comparison to the Me-DuPHOS complex, in particular when (Z)-configured β-acylamido acrylates were used as substrates.

Full text of DOI:10.1021/jo020453h

Syn th esis of a New Ch ir a l Bisp h osp h ola n e Liga n d for th e
Rh (I)-Ca ta lyzed En a n tioselective Hyd r ogen a tion of Isom er ic
â-Acyla m id o Acr yla tes
J ens Holz,*,† Axel Monsees,‡ Haijun J iao,† J insong You,† Igor V. Komarov,† Christine Fischer,†
Karlheinz Drauz,§ and Armin Bo¨rner*,†,|
Institut fu¨r Organische Katalyseforschung an der Universita¨t Rostock e.V., Buchbinderstr. 5/ 6,
18055 Rostock, Degussa AG, Projekthaus Katalyse, Industriepark Hoechst, Geba¨ude G 830,
65926 Frankfurt/ Main, Degussa AG, Business Unit Fine Chemicals, Postfach 13 54, 63403 Hanau,
Fachbereich Chemie der Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
jens.holz@ifok.uni-rostock.de; armin.boerner@chemie.uni-rostock.de
Received J uly 8, 2002
The highly stereoselective synthesis of a chiral silylphospholane has been described, which can be
advantageously used as a building block under base-free conditions for the construction of
diphosphines related to DuPHOS. The utility of silylphospholane is shown in the synthesis of a
new bisphospholane ligand 1 (MalPHOS), which is characterized by a maleic anhydride backbone.
The ligand forms with Rh(I) a complex with a larger bite angle P-Rh-P than the analogue Me-
DuPHOS complex. Both complexes have been tested in the asymmetric hydrogenation of unsatur-
ated R- and â-amino acid precursors of pharmaceutical relevance. In several cases, the new catalyst
was superior in comparison to the Me-DuPHOS complex, in particular when (Z)-configured
â-acylamido acrylates were used as substrates.
In tr od u ction
thesized by reaction of â-keto carboxylates with am-
monium salts and subsequent N-acylation. Interestingly,
although the preparation of R-amino acids by catalytic
hydrogenation is a well established procedure, even on
an industrial scale, only a few investigations have been
concerned with the Rh(I)-catalyzed enantioselective hy-
drogenation of prochiral â-acylamido acrylates.4,5 The
reason for this is probably the different behavior of
isomeric â-acylamido acrylates in the asymmetric hydro-
genation. Both isomers are produced simultaneously in
common synthetic protocols, and their individual hydro-
genation demands prior separation.
Although being less abundant than R-amino acids,
enantiopure â-amino acids represent compounds of broad
natural and pharmaceutical importance.1 In nature, they
are produced in different organisms either in a free form
or as part of peptides and depsipeptides. As components
of natural and unnatural compounds with interesting
antibiotic, antifungal, and cytotoxic properties,2 their
enantioselective synthesis is of increasing importance, in
particular for pharmaceutical chemistry.3
One of the most promising methods for the large-scale
preparation of enantiopure â-amino acids seems to be the
asymmetric hydrogenation of substituted â-acylamido
acrylates with Rh(I) catalysts bearing easily available
chiral phosphorus compounds as ancillary ligands. The
requisite prochiral substrates can be conveniently syn-
† Institut fu¨r Organische Katalyseforschung an der Universita¨t
Rostock e.V.
‡ Degussa AG, Projekthaus Katalyse.
§ Degussa AG, Business Unit Fine Chemicals.
In recent reports, we gave evidence that the asym-
metric hydrogenation of (E)- and (Z)-methyl 3-acetami-
dobutenoate employing a Rh(I) precatalyst with Me-
DuPHOS6 as a chiral ligand proceeds very fast and
| Fachbereich Chemie der Universita¨t Rostock.
(1) Sewald, N. In Bioorganic Chemistry, Highlights and New Aspects;
Diederichsen, U., Lindhorst, T. K., Westermann, B., Wessjohann, L.
A., Eds.; Wiley-VCH: Weinheim, Germany, 1999; Chapter 4.2, p 193.
Seebach, D.; Matthews, J . L. Chem. Commun. 1997, 2015.
(2) Ondetti, M. A.; Engel, S. L. J . Med. Chem. 1975, 18, 761.
Stachowiak, K.; Khosla, M. C.; Plucinska, K.; Khairallah, P. A.;
Bumpus, F. M. J . Med. Chem. 1979, 22, 1128.
(3) For reviews, see: Cole, D. C. Tetrahedron 1994, 50, 9517.
J uaristi, E. Enantioselective Synthesis of â-Amino Acids; Wiley-VCH:
New York, 1997; Sewald, N. Amino Acids 1996, 9, 397. See also:
Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1998, 9, 1341.
Saylik, D.; Campi, E. M.; Donohue, A. C.; J ackson, W. R.; Robinson,
A. J . Tetrahedron: Asymmetry 2001, 12, 657. Bull, S. D.; Davies, S.
G.; Smith, A. D. J . Chem. Soc., Perkin Trans. 1 2001, 2931.
(4) (a) Achiwa, K.; Soga, T. Tetrahedron Lett. 1978, 1119. (b) Lubell,
W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991, 2, 543.
(c) Zhu, G.; Chen, Z.; Zhang, X. J . Org. Chem. 1999, 64, 6907. (d) Lee,
S.-g.; Zhang, Y. J . Org. Lett. 2002, 4, 2429. (e) Tang, W.; Zhang, X.
Org. Lett. 2002, 4, 4159. (f) Pen˜a, D.; Minnaard, A. J .; de Vries, J . G.;
Feringa, B. L. J . Am. Chem. Soc. 2002, 124, 14552.
(5) Recently, excellent enantioselectivities were achieved with a
chiral Ru-catalyst: Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang,
X. J . Am. Chem. Soc. 2002, 124, 4952.
10.1021/jo020453h CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/12/2003
J . Org. Chem. 2003, 68, 1701-1707
1701

Holz et al.
produces the product with the same configuration.7
Under optimized conditions, methylâ-acetamido butyrate
was obtained in quantitative yield and by up to 98% ee.
Such excellent enantioselectivities were preferentially
achieved when the (E)-configured substrate was em-
ployed. In contrast, results attained in the hydrogenation
of the relevant (Z)-enamide, usually formed in a large
excess in synthetic protocols, were inferior. Since the
exchange of Me-DuPHOS by Et-DuPHOS only slightly
affected the enantioselectivity, we also tested oxyfunc-
tionalized analogues of DuPHOS such as Me4-BAS-
PHOS.8 Also, this alteration in the structure of the
phospholane moiety was not beneficial for the hydroge-
nation of the (Z)-substrate.
SCHEME 1
scaled up to industrial needs, has seen application in the
synthesis of several other C2-symmetric nonfunctional-
ized and functionalized bisphospholanes13 and related
bisphosphetanes.14 However, this approach is limited to
those primary diphosphines as nucleophilic reagents,
which are easily accessible. Obviously, due to the limited
selection of available diphosphines, the variation of the
bridge connecting both phospholane units, being decisive
for the proper adjustment of the bite angle of the ligand,
was strongly restricted up to now. Moreover, electrophiles
bearing other reactive functional groups such as carbonyl
groups cannot be employed because of the strong nucleo-
philicity of primary phosphides serving as reagents.
Highly promising for the synthesis of bisphospholanes
seems to be the use of a reactive monophospholane
reagent like 5, which could be coupled to a large variety
of dielectrophiles. A first attempt to establish such a
modular approach was reported by Burk et al.12 They
tried to generate lithium phosphide 5 by reductive
cleavage of the P-Ph bond in 4b with lithium. However,
this reaction was accompanied by the formation of P-P
coupling products12a and by epimerization at C2 and C5,
especially when larger alkyl substituents were linked to
these positions.12c,15 Moreover, when 5 was reacted with
propylene dichloride, only a poor yield of the desired
bisphospholane was achieved.16 As an alternative, sec-
ondary phospholane 4a was employed for the generation
Perusal of the literature in terms of homogeneous Rh-
(I)-catalysis indicates that fine-tuning of a catalyst may
also be achieved by variation of the bite angle of the
diphosphine ligand.9 A recent report by Orpen and
Pringle et al. showed that replacement of the phenylene
backbone in a DuPHOS-Rh-catalyst by 1,2-cyclopentane
changed significantly the enantioselectivity in the hy-
drogenation of unsaturated R-amino acid precursors.10
On the basis of this finding we envisaged the synthesis
of a new bisphospholane 1 (MalPHOS) bearing a maleic
anhydride backbone. The new ligand was prepared via
a new synthetic pathway and subsequently tested in the
enantioselective hydrogenation of several â-amino acid
precursors.
Resu lts a n d Discu ssion
Bisphospholanes of the DuPHOS type are commonly
synthesized by double nucleophilic substitution of an
appropriately substituted chiral cyclic 1,4-sulfate such
as 3 with o-phenylenediphosphine (Scheme 1).11 This
methodology originally disclosed by Burk is superior to
the use of corresponding 1,4-bissulfonates12 suffering
frequently by the formation of byproducts. In the past
decade, this straightforward method, which can be even
(6) Burk, M. J .; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee,
J . R.; Martinez, J . P. Pure Appl. Chem. 1996, 68, 37 and references
therein.
(7) Heller, D.; Holz, J .; Drexler, H.-J .; Lang, J .; Krimmer, H.-P.;
Drauz, K.; Bo¨rner, A. J . Org. Chem. 2001, 66, 6816. Heller, D.; Drexler,
H.-J .; You, J .; Drauz, K.; Krimmer, H.-P.; Bo¨rner, A. Chem. Eur. J .
2002, 8, 5196.
(8) Holz, J .; Stu¨rmer, R.; Schmidt, U.; Drexler, H.-J .; Heller, D.;
Krimmer, H.-P.; Bo¨rner, A. Eur. J . Org. Chem. 2001, 4615.
(9) Dierkes, P.; van Leeuwen, P. W. N. M. J . Chem. Soc., Dalton
Trans. 1999, 1519.
(10) Fernandez, E.; Gillon, A.; Heslop, K.; Horwood, E.; Hyett, D.
J .; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 1663.
(11) (a) Burk, M. J . J . Am. Chem. Soc. 1991, 113, 8518. (b) Burk,
M. J .; Feaster, J . E.; Nugent, W. A.; Harlowe, R. L. J . Am. Chem. Soc.
1993, 115, 10125.
(12) (a) Burk, M. J .; Feaster, J . E.; Harlow, R. L. Organometallics
1990, 9, 2653. (b) Burk, M. J .; Harlow, R. L. Angew. Chem., Int. Ed.
Engl. 1990, 29, 1462. (c) Burk, M. J .; Feaster, J . E.; Harlow, R. L.
Tetrahedron: Asymmetry 1991, 2, 569.
(13) (a) Achiral bisphospholanes: Field, L. D.; Thomas, I. P. Inorg.
Chem. 1996, 35, 2546. (b) Chiral bisphospholanes: (1) Nonfunction-
alized: Burk, M. J .; Gross, M. F. Tetrahedron Lett. 1994, 35, 9363.
Dierkes, P.; Ramdeehul, S.; Barloy, L.; De Cian, A.; Fischer, J .; Kamer,
P. C. J .; van Leeuwen, P. W. N. M.; Osborn, J . A. Angew. Chem., Int.
Ed. 1998, 37, 3116. (2) Functionalized: Holz, J .; Quirmbach, M.;
Schmidt, U.; Heller, D.; Stu¨rmer, R.; Bo¨rner, A. J . Org. Chem. 1998,
63, 8031. Carmichael, D.; Doucet, H.; Brown, J . M. Chem. Commun.
1999, 261. Li, W.; Zhang, Z.; Xiao, D.; Zhang, X. Tetrahedron Lett. 1999,
40, 6701. Yan, Y.-Y.; RajanBabu, T. V. J . Org. Chem. 2000, 65, 900.
Li, W.; Zhang, Z.; Xiao, D.; Zhang, X. J . Org. Chem. 2000, 65, 3489.
(14) 4. Marinetti, A.; Geneˆt, J . P.; J us, S.; Blanc, D.; Ratovelo-
manana-Vidal, V. Chem. Eur. J . 1999, 5, 1160. Berens, U.; Burk, M.
J .; Gerlach, A.; Hems, W. Angew. Chem., Int. Ed. 2000, 39, 1981.
Marinetti, A.; Carmichael, D. Chem. Rev. 2002, 102, 201.
(15) Burk, M. J .; Pizzano, A.; Martin, J . A.; Liable-Sands, L. M.;
Rheingold, A. L. Organometallics 2000, 19, 250.
1702 J . Org. Chem., Vol. 68, No. 5, 2003

New Chiral Bisphospholane Ligand
SCHEME 2
der the conditions of the P-Ph cleavage reaction, epimer-
ization at the chiral centers may occur, which leads in
our case finally to a mixture of a chiral and a meso-TMS-
phospholane 7. The degree of epimerization, also well-
known for 2,5-diphenylphospholane oxide derivatives
under basic conditions,20 varied from run to run. To rule
out that diastereomeric impurities in the commercial
starting diol are responsible for the formation of diastereo-
meric TMS-phospholanes, we used a mixture consisting
of racemic and meso-diol for the synthesis of 7. Under
these conditions, significant deviations of the diastereo-
selectivity of the TMS-phospholane from the diastereo-
meric purity of diol 2, its sulfate 3, and P-phenyl
phospholane 4b were noted. This gave clear evidence that
the epimerization takes place in the P-Ph cleavage step
and showed that phosphine 4b is not a suitable precursor
for optically pure TMS-phospholane 7. However, we were
pleased to see that the latter reacted cleanly with 2,3-
dichloromaleic anhydride 8 representing an activated
electrophile to give bisphospholane 1. Unexpectedly, the
reaction of a mixture of chiral and meso-phospholane 7
with dichloromaleic anhydride gave in all trials diaste-
reomerically pure 1. The 31P NMR spectrum of the
bisphosphine was characterized by a single resonance at
δ -2.2. Obviously the formation of bisphospholane 1
proceeds in a highly diastereoselective manner, avoiding
the formation of diastereomers with mixed configura-
tions.21
of 5.15 However, the former was revealed to be quite
volatile and difficult to isolate in good yield and pure
form.
More advantageous was the use of borane adducts of
4a and 4b reported by Burk15 and Achiwa,17 respectively.
Unfortunately, this method is limited to the preparation
of ligands with remote phospholane groups. Up to now,
the placement of two vicinal phosphine-borane groups at
a double bond could not be achieved, probably due to
steric reasons.18 In addition, the borane protection-
deprotection procedure prolongs the synthetic pathway
by two steps and decreases the overall yield.
In the next run, we prepared TMS-phospholane 7 by
reaction of sulfate 3 with P(SiMe3)3 in the presence of
methyllithium. The 31P NMR spectrum of compound 7
obtained in 70% yield showed only traces of the meso-
isomer (<2%), which can be traced back to a small
diastereomeric impurity of starting diol 2. TMS-Phos-
pholane 7 proved to be a remarkable stable reagent. It
could be distilled at 93 °C/20 mbar and stored under
argon without any tendency of epimerization. When this
building block was reacted with 2,3-dichloromaleic an-
hydride 8 in ethereal solution at 0 °C in the absence of
any base, a smooth and clean coupling reaction took
place. The optically pure ligand 1 could be precipated in
53% yield as dark-red crystals from the reaction solution.
Reaction of 1 with [Rh(COD)2]BF4 at -20 °C, being
necessary in order to rule out the formation of the bis-
ligand complex, afforded a precatalyst of the type [Rh-
(COD)(1)]BF4, which was characterized in the 31P NMR
spectrum by a doublet at δ 63.8 with a Rh-P coupling
constant of 151 Hz.
To compare the bite angle change from Me-DuPHOS
to 1, the structures of [Rh(COD)(Me-DuPHOS)]+ and
[Rh(COD)(1)]+ complexes and the free ligands were
optimized at the B3LYP level of density functional theory
with the LANL2DZ basis set as implemented in the
Gaussian 98 program (Figure 1).22 As expected, the PRhP
bite angle of the complex based on 1 (86.1°) is larger than
that of the Me-DuPHOS complex (83.6°).23 Compared
Another study of Burk and co-worker was focused on
the use of P-trimethylsilyl phospholane 7, which was
prepared from cyclic sulfate 3 by reaction with (TMS)2PLi
to give 6 and subsequent ring closure with MeLi.15
However, all trials to use this uncharacterized compound
as a source of phosphide anion 5 failed. The P-TMS bond
proved to be resistant to nucleophilic cleavage. This
failure is surprising, because the reaction of simple TMS-
diaryl- and -dialkylphosphines with chlorides was de-
scribed years ago by Fenske and Tillack.19
To determine if the low reactivity of TMS-phospholane
7 reported is associated with its unique ring structure,
we investigated its formation and reaction in more detail
(Scheme 2).
In a first trial, we generated 7 by treatment of 4b with
lithium and subsequent addition of TMS-Cl. Surpris-
ingly, the 31P NMR spectrum of 7 gave not a single
resonance as expected. Two signals at δ -53.0 and -54.5
in a ratio of 1:4 were found. This observation gave the
first hint related to an earlier report of Burk et al.12c that
even with 2,5-dimethyl-substituted phospholane 4b un-
(16) Low yields might be due to the reaction of the very reactive
Li-phosphide 5 with THF used as a solvent and its propensity to engage
in electron-transfer processes (ref 12).
(17) Morimoto, T.; Ando, N.; Achiwa, K. Synlett 1996, 1211.
(18) Schmidbaur, H.; Paschalidis, C.; Steigelmann, O.; Wilkinson,
D. L.; Mu¨ller, G. Chem. Ber. 1989, 122, 1857. Marinetti, A.; Kruger,
V.; Buzin, F. X. Tetrahedron Lett. 1997, 38, 2947. Ohff, M.; Holz, J .;
Quirmbach, M.; Bo¨rner, A. Synthesis 1998, 1391.
(19) Becher, H.-J .; Fenske, D.; Langer, E. Chem. Ber. 1973, 106,
177. Fenske, D.; Becher, H.-J . Chem. Ber. 1974, 107, 117. Fenske, D.;
Becher, H.-J . Chem. Ber. 1975, 108, 245. Becher, H.-J .; Fenske, D.;
Langer, E.; Prokscha, H. Monatshefte Chem. 1980, 111, 749. Kinting,
A.; Krause, H.-W. J . Organomet. Chem. 1986, 302, 259. Kinting, A.;
Do¨bler, C. J . Organomet. Chem. 1989, 370, 351. Tillack, A.; Michalik,
M.; Fenske, D.; Goesmann, H. J . Organomet. Chem. 1993, 454, 95.
For a review concerned with the synthesis and properties of silylphos-
phines, see: Fritz, G.; Scheer, P. Chem. Rev. 2000, 101, 3341.
(20) Fiaud, J .-C.; Legros, J .-Y. Tetrahedron Lett. 1991, 32, 5089.
Guillen, F.; Moinet, C.; Fiaud, J .-C. Bull. Soc. Chim. Fr. 1997, 143,
371. Hume, S. C.; Simpkins, N. S. J . Org. Chem. 1998, 63, 912. Guillen,
F.; Fiaud, J .-C. Tetrahedron Lett. 1999, 40, 2939.
(21) When such a ligand 1 derived from the reaction of a mixture
consisting of an excess of (R,R)-7 and some meso-7 with 2,3-dichloro-
maleic anhydride was used in a [Rh(COD)(1)]BF4 precatalyst for the
enantioselective hydrogenation of methyl (Z)-N-acetamido cinnamate
in MeOH, 94.0% ee was achieved.
J . Org. Chem, Vol. 68, No. 5, 2003 1703

Holz et al.
F IGURE 1. Comparison of bite angles of [Rh(COD)(Me-DuPHOS)]+ (a) and [Rh(COD)(1)]+ (b).
TABLE 1. En a n tioselective Hyd r ogen a tion of Sta n d a r d
to the benzene backbone in Me-DuPHOS, the five-
membered maleic anhydride backbone has a larger exo
PCdC angle (125.2° vs 118.8°). This in turn widens the
bite angle in [Rh(COD)(1)]+.24
a
Su bstr a tes w ith [Rh (COD)(liga n d )]BF 4
First, the new precatalyst was tested in the hydroge-
nation of standard substrates such as methyl (Z)-N-
acetamido cinnamate (9) and dimethyl itaconate (10) in
order to assess its catalytic performance. Relevant results
are listed in Table 1. For comparison, some results
obtained with the closely related Me-DuPHOS precata-
lyst are detailed.
As can be clearly seen, the catalyst derived from ligand
1 induces good or excellent enantioselectivities. However,
the ees achieved with the DuPHOS catalyst are mostly
higher, in particular when polar solvents have been used.
However, it is interesting to note that in several cases
a reversal of this order was found in the hydrogenation
of â-acylamido acrylates (Table 2).
ligand
substrate
(R,R)-1 (R,R)-Me-DuPHOS
compd R1
R2
solvent
MeOH 94.4 (R)
THF 98.6 (R)
CH2Cl2 97.9 (R)
toluol 98.4 (R)
CH2COOMe MeOH 60.2 (S)
THF 86.0 (S)
% ee
% ee
9
Ph NHAc
97.6 (R)
97.4 (R)
98.0 (R)
96.3 (R)
95.3 (S)
97.0 (S)
10
H
a
Conditions: 0.01 mmol of precatalyst and 1.0 mmol of prochiral
olefin in 15.0 mL of solvent at 25.0 °C, 1.0 atm overall pressure
over the solution, 1 h.
In particular for the hydrogenation of the important
(Z)-configured substrates bearing bulkier substituents in
the 3-position (Et, i-Pr, Ph), the new catalyst gave
significantly higher enantioselectivities. Differences of up
to 75% ee were found (compare, e.g., substrate (Z)-17),
whereas in the hydrogenation of relevant (E)-substrates
only marginal differences in the ee were noted for both
catalysts. In general, with increasing size of the sub-
stituent in the 3-position of (Z)-substrates, a decrease in
the enantioselectivity was observed, independent of the
catalyst and the solvent used. The nature of the acyl
groups (Ac, Bz) as well as electronic alterations in the
benzyl ester group did not significantly change the
enantioselectivity.
(22) . Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.; Montgomery, J . A.,
J r.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.; Millam, J . M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J .;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J . L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J . A. Gaussian 98, revision A.1; Gaussian, Inc.: Pittsburgh, PA,
1998.
(23) The bite angle of a [Rh(COD)(Me-DuPHOS)]SbF6 complex in
the crystal was found to be 84.7° (ref 11b). The difference from the
calculated value could be due to the effect of the counteranion SbF6.
(24) When the structures of the [Rh(COD)(Me-DuPHOS)]+ and [Rh-
(COD)(1)]+ complexes and the free ligands were free optimized by using
the PM3 semiempirical method as implemented in the Spartan
program (Spartan 2002; Wavefunction, Inc.: Irvine, CA, 2002), similar
angles were obtained: [Rh(COD)(1)]+, 85.8°; [Rh(COD)(Me-Du-
PHOS)]+, 82.8°. Exo PCdC angles: 1, 124.5°; Me-DuPHOS, 120.3°.
Con clu sion
In summary, the highly stereoselective synthesis of a
chiral silyl-substituted monophospholane has been de-
scribed, which can be advantageously used as an optically
pure building block under base-free conditions for the
construction of new bisphospholane ligands. The ap-
plicability of TMS-phospholane 7, which is available in
both enantiomeric forms, has been exemplarily proven
in the synthesis of a bisphospholane bearing a maleic
anhydride backbone. The new ligand 1 (MalPHOS) and
Rh(I) form a complex with a larger bite angle than a
related Me-DuPHOS complex. Both have been tested in
the asymmetric hydrogenation of unsaturated standard
substrates as a benchmark test and â-amino acid precur-
1704 J . Org. Chem., Vol. 68, No. 5, 2003

New Chiral Bisphospholane Ligand
a
TABLE 2. En a n tioselective Hyd r ogen a tion of â-Acyla m id o Acr yla tes w ith [Rh (COD)(liga n d )]BF 4
ligand
substrate
(R,R)-1
% ee
(R,R)-Me-DuPHOS
compd
R1
R2
R3
configuration
solvent
% ee
11
Me
Me
Me
Bn
Me
Z
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
83.0 (R)
83.5 (R)
97.9 (R)
97.8 (R)
83.9 (R)
79.1 (R)
98.1 (R)
98.0 (R)
89.9 (R)
85.2 (R)
>99.5 (R)
96.8 (R)
88.1 (R)
87.5 (R)
95.1 (R)
94.9 (R)
88.9 (R)
85.0 (R)
97.8 (R)
97.2 (R)
81.2 (R)
73.8 (R)
98.0 (R)
96.9 (R)
80.4 (S)
57.8 (S)
98.2 (S)
98.3 (S)
69.4 (S)
63.0 (S)
97.3 (S)
99.1 (S)
85.5 (S)
78.3 (S)
84.8 (S)
83.0 (S)c
84.8 (S)
81.6 (S)
83.3 (S)c
81.0 (S)c
81.7 (S)
83.0 (S)
84.2 (S)c
79.4 (S)c
87.8 (R)b
83.0 (R)
98.2 (R)b
98.8 (R)
83.5 (R)
67.1 (R)
96.6 (R)
98.3 (R)
84.3 (R)
81.6 (R)
>99.5 (R)
>99.5 (R)
85.6 (R)
82.7 (R)
>99.5 (R)
>99.5 (R)
84.2 (R)
82.2 (R)
98.7 (R)
97.3 (R)
68.4 (R)
58.1 (R)
99.4 (R)
99.6 (R)
3.7 (S)
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
12
13
14
15
16
17
18
19
20
21
Me
Me
Me
Me
Et
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
4-F-Bn
4-Me-Bn
Me
i-Pr
i-Pr
Ph
Me
22.5 (S)
98.7 (S)
98.4 (S)
3.6 (S)
Et
35.9 (S)
98.6 (S)
98.4 (S)
81.4 (S)
86.0 (S)
97.2 (S)
97.2 (S)c
78.0 (S)
73.0 (S)
98.3 (S)c
97.6 (S)c
75.9 (S)
74.8 (S)
96.9 (S)c
91.8 (S)c
Me
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
MeOH
THF
Ph
Et
Ph
4-Me-Bn
a
b
Conditions: see Table 1; time for hydrogenation < 3 h. From ref 7. c No complete conversion after 3 h.
16, 18, and 19 used as substrates were carried out following
known protocols.4b,c All reactions were performed under an
argon atmosphere by using standard Schlenk techniques.
Thin-layer chromatography was performed on precoated TLC
plates (silica gel). Flash chromatography was carried out with
silica gel 60 (particle size 0.040-0.063 mm). Melting points
are corrected. NMR spectra were recorded at the following
frequencies: 400.13 MHz (1H), 100.63 MHz (13C), 161.98 MHz
(31P). Chemical shifts of 1H and 13C NMR spectra are reported
in parts per million downfield from TMS as an internal
standard. Chemical shifts of 31P NMR spectra are referred to
H3PO4 as an external standard. Signals are quoted as s
(singlet), d (doublet), br (broad), and m (multiplet).
sors. In particular, in the hydrogenation of pharmaceuti-
cally important (Z)-configured â-dehydroamino acid de-
rivatives, the new catalyst was mostly superior in
comparison to the Me-DuPHOS complex. Our results
clearly demonstrate that for each substrate, an individual
catalyst has to be identified in order to induce the
maximum enantioselectivity. Therefore, the search for
synthetic routes that allow the facile modular construc-
tion of ligands represents a great challenge in future
asymmetric catalysis. Work is in progress to show the
versatility of TMS-phospholanes also for the synthesis
of other ligands.
Hydrogenation experiments have been carried out under
normal pressure and isobaric conditions with an automatically
registering gas measuring device (1.0 atm overall pressure over
the solution). The experiments were performed with 0.01 mmol
of precatalyst and 1.0 mmol of prochiral olefin in 15.0 mL of
Exp er im en ta l Section
Gen er a l. Solvents were dried and freshly distilled under
argon before use. The syntheses of â-acylamido acrylates 11,
J . Org. Chem, Vol. 68, No. 5, 2003 1705

Holz et al.
solvent at 25.0 °C. The conversion of the prochiral R- and
â-dehydroamino acids and the reduction of dimethyl itaconate
and their % ees were determined by GC or HPLC. Methyl (Z)-
acetamido cinnamate (9): 25 m Lipodex E, 145 °C. Dimethyl
itaconate (10): 25 m Lipodex E, 80 °C. Methyl 3-acetamido
butenoate (11): 50 m Chiraldex â-PH, 130 °C. Methyl 3-benz-
amido butenoate (12): Chiralcel OB, 90:10 hexane/EtOH.
Benzyl 3-acetamido butenoate (13): CHIRALCEL OD-H, 95:5
hexane/EtOH. 4-Fluoro-benzyl 3-acetamido butenoate (14):
CHIRALCEL OJ , 95:5 hexane/EtOH. 4-Methyl-benzyl 3-ac-
etamido butenoate (15): CHIRALCEL OJ , 90:10 hexane/
EtOH. Methyl 3-acetamido pentenoate (16): 25 m, Lipodex
E, 130 °C. Methyl 4-methyl-3-acetamido-2-pentenoate (17): 25
m, Lipodex E, 130 °C. Ethyl 4-methyl-3-acetamido-2-penten-
oate (18): 25 m, Lipodex E, 130 °C. Methyl 3-phenyl-3-
acetamido propenoate (19): CHIRALCEL OD-H, 96:4 hexane/
EtOH. Ethyl 3-phenyl-3-acetamido propenoate (20): CHIRAL-
CEL OD-H, 95:5 hexane/EtOH. 4-Methyl-benzyl 3-phenyl-3-
acetamido propenoate (21): CHIRALPAK AD, 95:5 hexane/
EtOH.
94.9 (m), 108.5 (m), 160.1 (m) and 165.1 (m); 31P NMR δ 63.8
1
(d, J P,Rh ) 151 Hz); C24H36O3P2RhBF4 (624.20).
Meth yl 3-Ben za m id o-2-bu ten oa te (12). To a solution of
methyl 3-aminocrotonate (2.0 g, 17.4 mmol) and pyridine (2.1
g, 26.1 mmol) in ether (30 mL) was slowly added 1 equiv of
benzoyl chloride (2.45 g). The mixture was stored overnight
in a refrigerator. Workup was carried out by dillution with
ether (20 mL) and washing of the organic phase with water
(10 mL), 1 N HCl (10 mL), and brine (10 mL). After drying
and evaporation of the solvent, the raw product was purified
by column chromatography with a gradient of n-hexane/ethyl
acetate (from 9:1 to 4:1). The yields were 1.0 g of the (Z)-isomer
(26%) and 1.2 g of the (E)-isomer (32%).
1
(Z)-Isom er : mp ) 55-57 °C; H NMR (acetone-d6) δ 2.50
(3H), 3.72 (3H, s), 5.10 (1H, s), 7.55-7.67 (3H, m), 7.98 (2H,
m), 12.14 (1H, s(br)); 13C NMR (acetone-d6) δ 21.9, 51.5, 97.2,
128.3, 129.8, 133.3, 135.0, 156.5, 165.3, 170.6. Anal. Calcd for
C
12H13O3N (219.24): C, 65.74; H, 5.98; N, 6.39. Found: C,
66.06; H, 6.17; N, 5.83.
(E)-Isom er : mp ) 109-113 °C; 1H NMR (acetone-d6) δ 2.50
(3H, s), 3.64 (3H, s), 7.03 (1H, s), 7.46-7.60 (3H, m), 7.89 (2H,
m), 9.03 (1H, s(br)); 13C NMR (acetone-d6) δ 18.1, 50.8, 102.4,
128.4, 129.3, 132.7, 135.6, 151.6, 167.3, 169.0. Anal. Calcd for
(R,R)-2,5-Dim et h yl-1-t r im et h ylsilyl-p h osp h ola n e (7).
To a solution of tris(trimethylsilyl)phosphine25 (9.5 g, 37.9
mmol) in THF (300 mL) was slowly added a 1.4 M solution of
methyllithium (1.05 equiv, 28.4 mL) in ether. After the mixture
was stirred overnight, the solvent was evaporated under
reduced pressure and the residue dissolved in ether (300 mL).
Cyclic sulfate 3 (6.83 g, 37.9 mmol) dissolved in ether (100
mL) was added dropwise to the lithium-salt solution, and after
3 h a second equivalent of methyllithium solution (28.4 mL)
was added slowly via a syringe. For completion of the reaction,
the solution was stirred overnight and then the ether removed
by evaporation. The residue was carefully distilled in vacuo
to give the desired TMS-phospholane in a yield of 70% (5.0 g).
The compound starts burning immediately in air and should
be therefore handled carefully under argon: bp ) 93 °C/20
C
12H13O3N (219.24): C, 65.74; H, 5.98; N, 6.39. Found: C,
65.88; H, 6.10; N, 6.29.
Ben zyl 3-Aceta m id o-2-bu ten oa te (13). According to the
protocol of Zhang et al.,4c benzyl acetylacetate (2.31 g, 12 mmol)
was dissolved in methanol (20 mL). The solution was stirred
over a period of 3 days with NH4OAc (4.6 g, 60 mmol). The
workup was performed as described. The product was treated
with pyridine (2 mL) and acetic anhydride (6 mL) in THF (15
mL). The product thus obtained was treated with a 1:1 mixture
of n-hexane/ether to give the (E)-isomer as a white product
(0.95 g, 34%). The filtrate was concentrated, and after column
chromatography with a gradient of n-hexane/ethyl acetate
(from 4:1 to 1:1), the (Z)-isomer of 13 (1.20 g, 43%) and
additional (E)-isomer (0.15 g, 5%) could be isolated.
mbar; [R]23 ) +132° (c 2.5, CH2Cl2); 1H NMR (CDCl3) δ 0.20
D
(9H, d, 3J H,P ) 4.2 Hz), 1.25-1.15 (6H, m), 2.54-1.20 (6H, m);
2
2
13C NMR (CDCl3) δ -0.2 (d, J C,P ) 11.4 Hz), 18.0 (d, J C,P
)
1
(Z)-Isom er : mp ) 50-53 °C; H NMR (acetone-d6) δ 2.11
2
1
1.9 Hz), 22.8 (d, J C,P ) 30.5 Hz), 31.3 (d, J C,P ) 7.6 Hz), 33.6
(3H, s), 2.34 (3H, s), 4.99 (1H, s), 5.17 (2H, s), 7.29-7.40 (5H,
m), 11.03 (1H, s(br)); 13C NMR (acetone-d6) δ 21.1, 25.1, 65.9,
95.9, 128.8, 128.9, 129.3, 137.5, 156.6, 169.4, 169.1. Anal. Calcd
for C13H15O3N (233.27): C, 66.94; H, 6.48; N, 6.00. Found: C,
66.69; H, 6.23; N, 5.83.
(d, J C,P ) 11.4 Hz), 38.9 (s), 40.1 (d, J C,P ) 4.8 Hz); 31P NMR
(CDCl3) δ -54.5; C9H21PSi (188.32). Due to the high flamabil-
ity, elemental analysis could not be performed.
1
1
2,3-Bis[(R,R)-2,5-d im et h yl-p h osp h ola n yl]m a leic An -
h yd r id e (1). TMS-Phospholane 7 (0.55 g, 2.91 mmol) dissolved
in ether (1.5 mL) was added by a cannula dropwise over a
period of 15 min to a solution of 0.5 equiv of 2,3-dichloromaleic
anhydride (0.24 g, 1.45 mmol) in ether (2 mL) at 0 °C. The
suspension was stored at -78 °C for 3 days, and the precipi-
tated dark-red crystals were filtered off and dried. The yield
of compound 1 was 0.25 g (53%): 1H NMR (CDCl3) δ 1.06 (6H,
(E)-Isom er : mp ) 104-106 °C; 1H NMR (acetone-d6) δ 2.02
(3H, s), 2.30 (3H, s), 5.09 (2H, s), 6.92 (1H, s), 7.27-7.39 (5H,
m), 8.76 (1H, s(br)); 13C NMR (acetone-d6) δ 18.1, 24.6, 65.4,
100.9, 128.5, 128.7, 129.2, 138.2, 151.7, 168.5, 170.1. Anal.
Calcd for C13H15O3N (233.27): C, 66.94; H, 6.48; N, 6.00.
Found: C, 66.77; H, 6.25; N, 5.89.
4-F lu or o-ben zyl 3-Aceta m id o-2-bu ten oa te (14). A solu-
tion of ethyl acetoacetate (13.0 g, 0.1 mol) and 4-fluoro benzyl
alcohol (12.6 g, 0.1 mol) in toluene (200 mL) was heated under
reflux over a period of 16 h. During this time, a mixture of
toluene/ethanol was distilled slowly. Finally, the solvent was
removed and the residue was distilled to give 4-fluoro-benzyl
acetoacetate (Kp0.3 ) 110-115 °C).
3
3
3
dd, J H,P ) 10.5 Hz, J H,H ) 7.1 Hz), 1.22 (6H, dd, J H,P ) 20.4
Hz, 3J H,H ) 7.2 Hz), 2.49-1.25 (12H, m), 3.32 (2H, m); 13C NMR
(CDCl3) δ 16.8 (s), 20.5 (m), 31.5 (s), 36.6 (m), 36.9 (s), 37.6
(s), 158.9 (m), 163.6 (s); 31P NMR (CDCl3) δ -2.2; C16H24O3P2
(326.31).
[Rh (COD)(1)]BF 4. Bisphospholane 1 (0.19 g, 0.58 mmol)
was dissolved in THF (2 mL) and slowly added to a suspension
of [Rh(COD)2]BF4 (0.24 g, 0.58 mmol) in THF (2 mL) at -20
°C. The mixture was allowed to warm at ambient temperature.
During this time, a brown solid precipitated, which was filtered
off. After the solid was washed with ether (2 × 5 mL) and dried
under reduced pressure, 0.22 g (62%) of the precatalyst were
obtained. If necessary, product could be purified by recrystal-
lization from CH2Cl2/ether: 1H NMR (acetone-d6) δ 1.23 (6H,
Related to the procedure of Zhang et al.,4c 4-fluoro-benzyl
acetoacetate was transformed into (E)-/(Z)-isomers of 4-fluoro-
benzyl 3-acetamido-butenoate (14) as described above for
compound 13. The separation of isomers was carried out by
column chromatography with a gradient of n-hexane/ethyl
acetate (from 4:1 to 1:1). The yield of the (Z)-isomer was 1.35
g (45%), and that of the (E)-isomer was 1.0 g (33%).
1
(Z)-Isom er : mp ) 88-92 °C; H NMR (acetone-d6) δ 2.11
3
3
3
dd, J H,P ) 16.0 Hz, J H,H ) 7.1 Hz), 1.57 (6H, dd, J H,P ) 19.5
(3H, s), 2.33 (3H, s), 4.97 (1H, s), 5.15 (2H, s), 7.13 (2H, m),
7.45 (2H, m), 11.00 (1H, s(br)); 13C NMR (acetone-d6) δ 21.9,
25.1, 65.2, 95.9, 116.0 (d, J ) 21 Hz), 131.2 (d, J ) 9 Hz), 133.6
(d, J ) 4 Hz), 156.7, 163.3 (d, J ) 244 Hz), 169.1, 169.3. Anal.
Calcd for C13H14O3FN (251.26): C, 62.14; H, 5.62; N, 5.57.
Found: C, 62.28; H, 5.34; N, 5.38.
3
Hz, J H,H ) 7.0 Hz), 2.67-1.50 (18 H, m), 3.07 (2H, m), 5.15
(2H, s(br)), 5.85 (2H, s(br)); 13C NMR (acetone-d6) δ 14.1 (s),
17.6 (m), 29.0 (s), 32.8 (s), 36.4 (s), 37.7 (s), 38.0 (m), 40.8 (m),
(25) Popova, E. V.; Patsanovskii, I. I.; Livantsov, M. V.; Ishmaeva,
E. A. Russ. J . Gen. Chem. 1996, 66, 1369; Zh. Obshch. Khim. 1996,
66, 1369.
(E)-Isom er : mp ) 130-133 °C; 1H NMR (acetone-d6) δ 2.04
(3H, s), 2.30 (3H, s), 5.09 (2H, s), 6.93 (1H, s), 7.13 (2H, m),
1706 J . Org. Chem., Vol. 68, No. 5, 2003

New Chiral Bisphospholane Ligand
7.45 (2H, m), 8.79 (1H, s(br)); 13C NMR (acetone-d6) δ 18.1,
24.6, 64.7, 100.8, 115.8 (d, J ) 21 Hz), 131.0 (d, J ) 8 Hz),
134.3 (d, J ) 3 Hz), 151.8, 163.2 (d, J ) 244 Hz), 168.5, 170.1.
Anal. Calcd for C13H14O3FN (251.26): C, 62.14; H, 5.62; N,
5.57. Found: C, 62.23; H, 5.75; N, 5.47.
at 0 °C a solution of acetyl chloride (1.56 g, 20 mmol) in ether
(10 mL). The mixture was warmed to ambient temperature,
and stirring was continued for 48 h. For the workup, the
mixture was diluted with ether (25 mL) and poored in ice-
water (20 mL). The ether phase was washed with 1 N HCl
(15 mL), saturated NaHCO3 (15 mL), and brine (15 mL). After
drying (Na2SO4) and evaporation of the solvent, the raw
product was purified as described above. The yields were 0.75
g of the (Z)-isomer (32%) and 0.48 g of the (E)-isomer (21%).
4-Meth yl-ben zyl 3-Aceta m id o-2-bu ten oa te (15). Accord-
ing to the synthesis of 14, ethyl acetoacetate (13.0 g, 0.1 M)
and 4-methylbenzyl alcohol (12.2 g, 0.1 M) in toluene (200 mL)
were heated. After removal of the solvent, the residue was
distilled to give 4-methyl-benzyl acetoacetate (Kp0.3 ) 110-
112 °C). Related to the procedure of Zhang et al.,4c 4-methyl-
benzyl acetoacetate was transformed into the (E)-/(Z)-isomers
of 4-methyl-benzyl 3-acetamido-butenoate (15) as described
above for compound 13. The separation of the isomers was
carried out by column chromatography with a gradient of
n-hexane/ethyl acetate (from 2:1 to 1:1). The yield of the (Z)-
isomer was 1.05 g (35%), and that of the (E)-isomer was 1.2 g
(39%).
1
(Z)-Isom er : mp ) 42-45 °C; H NMR (acetone-d6) δ 1.28
(3H, t 3J ) 7.1 Hz), 2.12 (3H, s), 4.20 (2H, q, 3J ) 7.1 Hz),
5.28 (1H, s), 7.33-7.44 (5H, m), 10.46 (1H, s(br)); 13C NMR
(acetone-d6) δ 14.5, 24.5, 60.7, 101.6, 128.0, 128.7, 130.1, 137.3,
155.2, 168.5, 168.7. Anal. Calcd for C13H15O3N (233.27): C,
66.94; H, 6.48; N, 6.00. Found: C, 66.89; H, 6.24; N, 5.94.
(E)-Isom er : mp ) 106-109 °C; 1H NMR (acetone-d6) δ 1.04
(3H, t 3J ) 7.1 Hz), 2.11 (3H, s), 3.89 (2H, q, 3J ) 7.1 Hz),
7.11 (1H, s), 7.29-7.46 (5H, m), 8.68 (1H, s(br)); 13C NMR
(acetone-d6) δ 14.4, 24.6, 59.5, 103.4, 128.6, 129.4, 129.5, 137.5,
150.9, 167.3, 170.4. Anal. Calcd for C13H15O3N (233.27): C,
66.94; H, 6.48; N, 6.00. Found: C, 66.72; H, 6.32; N, 5.88.
4-Meth yl-ben zyl 3-Aceta m id o-3-p h en yl-2-p r op en oa te
(21). A solution of ethyl benzoyl acetate (19.2 g, 0.1 mol) and
4-methylbenzyl alcohol (12.2 g, 0.1 mol) in toluene (200 mL)
was heated under reflux over a period of 16 h. During this
time, a mixture of toluene/ethanol was distilled slowly. Finally,
the solvent was removed and the residue was distilled to give
4-methyl-benzyl benzoyl acetate (Kp0.3 ) 178-185 °C). The
â-ketoester (3.2 g, 12 mmol) was transformed into 4-methyl-
benzyl 3-amino-3-phenyl-2-propenoate by stirring with NH4-
OAc (4.6 g, 60 mmol) in methanol (40 mL) over a period of 3
days at ambient temperature. After workup as described,4c the
raw product was dissolved in a mixture of ether (30 mL) and
pyridine (1.90 g, 24 mmol) at 0 °C. A solution of 2 equiv of
acetyl chloride (1.88 g) in ether (10 mL) was added slowly via
a syringe over a period of 30 min. During this time, a white
solid precipitated (pyridinium chloride). The mixture was
stirred at room temperature for 3 days. Then, the mixture was
diluted with additional ether (50 mL) and poored in ice-water
(30 mL). After phase separation, the ethereal solution was
washed with 1 N HCl (20 mL), saturated NaHCO3 (20 mL),
and brine (25 mL). After drying with Na2SO4 and evaporation
of the solvent, the raw product was purified by chromatogra-
phy with a gradient of n-hexane/ethyl acetate (from 4:1 to 1:1)
and yielded the (Z)-isomer (0.95 g, 26%) and the (E)-isomer
(0.73 g, 20%).
1
(Z)-Isom er : mp ) 49-53 °C; H NMR (acetone-d6) δ 2.10
(3H, s), 2.32 (3H, s), 2.33 (3H, s), 4.96 (1H, s), 5.11 (2H, s),
7.18 (2H, m), 7.27 (2H, m), 11.04 (1H, s(br)); 13C NMR (acetone-
d6) δ 21.1, 21.9, 25.1, 65.9, 96.0, 129.0, 129.9, 134.4, 138.5,
156.4, 169.1, 169.4. Anal. Calcd for C14H17O3N (247.30): C,
68.00; H, 6.93; N, 5.66. Found: C, 68.20; H, 6.76; N, 5.46.
1
(E)-Isom er : mp ) 78-80 °C; H NMR (acetone-d6) δ 2.03
(3H, s), 2.31 (3H, s), 2.32 (3H, s), 5.06 (2H, s), 6.92 (1H, s),
7.16 (2H, m), 7.28 (2H, m), 8.77 (1H, s(br)); 13C NMR (acetone-
d6) δ 18.1, 21.1, 24.6, 65.3, 101.1, 128.9, 129.7, 135.1, 138.1,
151.5, 168.5, 170.1. Anal. Calcd for C14H17O3N (247.30): C,
68.00; H, 6.93; N, 5.66. Found: C, 68.12; H, 6.75; N, 5.67.
Meth yl 4-Meth yl-3-a ceta m id o-2-p en ten oa te (17). Ac-
cording to the protocol of Zhang et al.,4c methyl 4-methyl-3-
oxo-pentanoate (1.73 g, 12 mmol) was dissolved in methanol
(20 mL) and stirred over a period of 3 days with NH4OAc (4.60
g, 60 mmol). After workup as described, the residue was
treated with pyridine (2 mL) and acetic anhydride (6 mL) in
THF (15 mL). The raw product obtained was purified by
column chromatography with a gradient of n-hexane/ethyl
acetate (from 4:1 to 1:1) to give the (Z)-isomer (0.85 g, 38%)
and the (E)-isomer (0.68 g, 31%).
(Z)-Isom er : liquid, 1H NMR (acetone-d6) δ 1.10 (6H, d), 2.11
(3H, s), 3.68 (3H, s), 5.04 (1H, s), 11.10 (1H, s(br)); 13C NMR
(acetone-d6) δ 21.5, 25.4, 29.9, 51.3, 92.3, 166.3, 169.6, 170.5.
Anal. Calcd for C9H15O3N (185.23): C, 58.36; H, 8.16; N, 7.56.
Found: C, 58.27; H, 7.88; N, 7.42.
1
(E)-Isom er : mp ) 62-65 °C; H NMR (acetone-d6) δ 1.13
1
(6H, d), 2.09 (3H, s), 3.59 (3H, s), 4.34 (1H, q), 6.98 (1H, s),
8.15 (1H, s(br)); 13C NMR (acetone-d6) δ 19.7, 24.7, 27.9, 50.7,
100.5, 159.0, 168.8, 170.8. Anal. Calcd for C9H15O3N (185.23):
C, 58.36; H, 8.16; N, 7.56. Found: C, 58.48; H, 7.77; N, 7.33.
Eth yl 3-Aceta m id o-3-p h en yl-2-p r op en oa te (20). Ethyl
benzoyl acetate (2.31 g, 12 mmol) was transformed in a two-
step procedure into ethyl 3-acetamido-3-phenyl-butenoate. The
raw product was purified by column chromatography with a
gradient of n-hexane/ethyl acetate (from 4:1 to 1:1). Besides
the unchanged intermediate, ethyl 3-amino-3-phenyl-prope-
noate, the desired (Z)-20 (1.26 g, 45%) was obtained. The (E)-
isomer could only be isolated in a low yield (0.15 g, 5%).
The yield of the (E)-isomer could be improved by application
of another acetylation procedure described for the synthesis
of methyl 3-acetamido-butenoate (11).26 Thus, to a solution of
ethyl-3-amino-phenylpropenoate (1.91 g, 10 mmol) and pyri-
dine (1.78 g, 20 mmol) in ether (20 mL) was added dropwise
(Z)-Isom er : mp ) 74-77 °C; H NMR (acetone-d6) δ 2.12
(3H, s), 2.33 (3H, s), 5.19 (2H, s), 5.33 (1H, s), 7.20-7.45 (9H,
m), 10.42 (1H, s(br)); 13C NMR (acetone-d6) δ 21.1, 24.5, 66.3,
101.5, 128.0, 128.7, 129.2, 129.9, 130.2, 134.3, 137.3, 138.6,
155.6, 168.5, 168.5; Anal. Calcd for C19H19O3N (309.37): C,
73.77; H, 6.19; N, 4.53. Found: C, 73.57; H, 5.88; N, 5.52.
(E)-Isom er : mp ) 128-132 °C; 1H NMR (acetone-d6) δ 2.11
(3H, s), 2.30 (3H, s), 4.90 (2H, s), 7.17 (1H, s), 7.13-7.39 (9H,
m), 8.69 (1H, s(br)); 13C NMR (acetone-d6) δ 21.1, 24.6, 65.5,
103.0, 128.7, 128.8, 129.5, 129.6, 129.7, 134.8, 137.4, 138.0,
151.4, 167.3, 170.4. Anal. Calcd for C19H19O3N (309.37): C,
73.77; H, 6.19; N, 4.53. Found: C, 73.74; H, 5.99; N, 4.49.
Ack n ow led gm en t. The authors are grateful for the
financial support provided by the Bmbf (03C0304A),
Degussa AG (Du¨sseldorf), and the Fonds der Chemis-
chen Industrie. I.K. is thankful for a grant given by the
Humboldt foundation. It is a pleasure for us to acknowl-
edge the skilled technical assistance of Mrs. G. Wenzel
and Mrs. S. Buchholz.
(26) Shabana, R.; Rasmussen, J . B.; Lawesson, S.-O. Bull. Soc.
Chim. Belg. 1981, 90, 75. Yakimovich, S. I.; Kajukova, L. A.; Chrust-
aljev, W. A.; Zazenkina, L. A. J . Org. Chem. USSR 1977, 13, 1069;
Zh. Org. Khim. 1977, 13, 1161. Grob, C. A. Helv. Chim. Acta 1950, 33,
1787.
J O020453H
J . Org. Chem, Vol. 68, No. 5, 2003 1707