Bispalladacycle-Catalyzed Michael Addition
FULL PAPER
5.40 mmol, 13.1 mg in 200 mL HOAc/Ac2O (70:30)) were successively
added to this mixture The resulting slurry was heated to 308C. After 23 h
the reaction mixture was cooled to room temperature and was directly
used for silica gel column chromatography.
Conclusion
In conclusion, we have reported the first catalytic asymmet-
ric conjugate additions of azlactones to enones. This task
was accomplished by the cooperative activation by a bis-Pd
catalyst, a Brønsted acid (acetic or benzoic acid), and a
Brønsted base (NaOAc). Kinetic studies revealed that the
azlactone is in a rapid equilibrium with the corresponding
acyclic mixed anhydride by ring-opening with acetic acid.
Due to the remarkable robustness of the bis-Pd catalyst to-
wards acetic anhydride, this equilibrium could be explored
to develop a tandem azlactone formation/Michael addition
process starting from racemic N-benzoylated tertiary amino
acids. The next evolution stage involved a tandem process,
which is capable to directly transform unprotected racemic
a-amino acids into the masked and activated highly enan-
tioenriched quaternary amino acid products bearing an addi-
tional tertiary stereocenter. This sequence implies both an
N- and O-amino acid acylation, a cyclization to form race-
mic azlactones, an enolization, and the asymmetric addition
to the enone. The methodology offers a broad variability
and provides rapid access to biologically interesting unnatu-
ral quaternary amino acid derivatives in a single step from
inexpensive bulk chemicals. The synthetic utility of the con-
jugate addition products was showcased by the rapid and di-
vergent formation of various quaternary amino acid deriva-
tives like an acyclic unmasked a-amino acid, a-alkyl proline,
and pyroglutamic acid derivatives. Moreover two comple-
mentary routes to biologically interesting a-alkyl glutamic
acid derivatives have been developed and we have demon-
strated that diastereomerically pure bicyclic dipeptides are
accessible in just two steps from unprotected tertiary a-
amino acids.
General procedure for the catalytic asymmetric synthesis of a,a-disubsti-
tuted amino acid derivatives by using unprotected amino acids: The cor-
responding racemic amino acid 6 (1.00 equiv, 0.20 mmol), the correspond-
ing enone
2 (6.00 equiv, 1.20 mmol), NaOAc (0.25 equiv, 50.0 mmol,
4.10 mg), benzoic acid (35 equiv, 7.00 mmol, 855 mg), and benzoic anhy-
dride (20 equiv, 4.00 mmol, 905 mg) were successively charged into a
flask. The activated catalyst [FBIP-Cl]2 was added to this mixture as a
stock solution in THF/PhMe (0.03 equiv, 6.00 mmol, 14.6 mg in 440 mL
THF/PhMe (10:1)). The resulting slurry was heated to 708C under vigo-
rous stirring for 7 h. After this time, the mixture was cooled to room tem-
perature. The solidified crude product was taken up in CH2Cl2 (ꢂ20 mL)
and was washed once with saturated aqueous NaHCO3. The organic
layer was separated, dried over Na2SO4, filtered, and concentrated. The
targeted amino acid derivative was purified by silica gel column chroma-
tography. To completely remove benzoic anhydride, the fractions contain-
ing the target product were concentrated and subjected to another silica
gel column. Remaining benzoic acid was removed by washing the frac-
tions containing the target product with saturated aqueous solution of
NaHCO3, and then Na2SO4 was used for drying.
General procedure for the recycling of the FBIP catalyst: The activated
catalyst (2 mol%, 1 mmol, 2.43 mg) was added as stock solution in acetic
acid/acetic anhydride (7:3, 150 mL) to N-benzoyl norvaline (5-Ph-c)
(1.0 equiv, 50.0 mmol, 11.1 mg), trans-4-phenyl-but-3-en-2-one (2A)
(2.0 equiv, 100 mmol, 14.6 mg), and sodium acetate (10 mol%, 5.0 mmol,
0.4 mg). The resulting mixture was warmed to 308C for the indicated
time and then cooled to room temperature. After removal of the vola-
tiles, n-hexane was added (15ꢃ5 mL) to extract the residue. The liquid
was concentrated and the crude product was used for the determination
of conversion and yield (1H NMR spectroscopic analysis by using mesity-
lene (7.22 equiv, 0.36 mmol, 43.4 mg, 50 mL) as internal standard) and
was purified by silica gel chromatography (petrol ether/ethyl acetate 7:3).
The isolated product was used to determine the enantiomeric excess of 3-
Ph-cA by chiral HPLC (Chiracel AD-H, n-hexane/iPrOH (98:2),
0.7 mLminꢁ1, detection at 245 nm (14.0 min minor enantiomer, 20.2 min
major enantiomer)). For the next catalytic run, the flask containing the
catalyst was then directly charged with N-benzoyl norvaline (5-Ph-c)
(1.0 equiv, 50.0 mmol, 11.1 mg) and trans-4-phenyl-but-3-en-2-one (2A)
(2.0 equiv, 100 mmol, 14.6 mg). Acetic acid/acetic anhydride (7:3, 150 mL)
was added to this mixture and the resulting solution was heated to 308C.
All following manipulations were performed as described above.
Experimental Section
Activation of the precatalyst [FBIP-Cl]2: [FBIP-Cl]2 (1 equiv) and the
corresponding silver salt (4 equiv) were suspended/dissolved in acetoni-
trile (1 mL per 5 mg [FBIP-Cl]2) and stirred for 6 h at room temperature.
The reaction flask was covered with aluminum foil to shield it from light
during that period. Subsequently, the mixture was filtered through celite
and free acetonitrile was removed under reduced pressure (ca. 5 min at
15 mbar and room temperature). A stock solution was subsequently pre-
pared.
Acknowledgements
This work was financially supported by the Deutsche Forschungsgemein-
schaft (DFG, PE 818/4-1).
General procedure for the catalytic asymmetric synthesis of a,a-disubsti-
tuted amino acid derivatives starting from isolated azlactones: Stock solu-
tions of NaOAc (0.1 equiv, 270 mmol, 2.21 mg in 500 mL AcOH/Ac2O
(70:30)) and the activated catalyst [FBIP-Cl]2 (0.02 equiv, 5.40 mmol,
13.1 mg in 310 mL AcOH/Ac2O (70:30)) were added to the corresponding
racemic azlactone 1-Ph (1.0 equiv, 0.27 mmol), followed by the addition
of the corresponding enone 2 (2.0 equiv, 0.54 mmol). The resulting mix-
ture was warmed to 308C for 23 h. After cooling to room temperature,
the crude product was directly used for silica gel chromatography.
[1] a) J. Venkatraman, S. C. Shankaramma, P. Balaram, Chem. Rev.
1993, 32, 1244; c) M. C. Khosla, K. Stachowiak, R. R. Smeby, F. M.
General procedure for the catalytic asymmetric synthesis of a,a-disubsti-
tuted amino acid derivatives starting from N-benzoyl amino acids: The
corresponding enone 2 (2 equiv, 0.54 mmol) was added to the corre-
sponding racemic N-benzoyl amino acid 5-Ph (1 equiv, 0.27 mmol) at
88C. Stock solutions of NaOAc (0.1 equiv, 27.0 mmol, 2.21 mg in 125 mL
AcOH/Ac2O (70:30)) and the activated catalyst [FBIP-Cl]2 (0.02 equiv,
[4] Selected examples for allylic alkylations: a) B. M. Trost, X. Ariza, J.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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