subject has been extensively reviewed by Cativiela.3 Of these
known methods, Seebach’s self-regeneration of stereocenters
principle4 in preparation of R-substituted amino acid deriva-
tives was most attractive to us due to its simplicity in terms
of the easy access of the chiral template imidazolidinones
(up to 90% ds), the stability of its enolate at higher
temperature (up to 0 °C), and the predictability of its
stereochemical outcome. Unfortunately, this method has not
been widely used, especially for industrial large-scale
production, mainly due to the harsh conditions (aqueous HCl,
150-220 °C) required to hydrolyze the resulting 5,5-
disubstituted imidazolidinone,5-15 as well as its modest
diastereoselectivities (70-90% ds) in the formation of the
imidazolidinone template.5 In this Letter, we wish to report
an efficient enantiospecific synthesis of BIRT-377 (1) based
on a modification of Seebach’s strategy in which we extend
the original protocol to achieve complete (>99.9%) overall
stereoselectivity.
Scheme 2
During our survey in the literature, it was found that the
stereoselective formation of either the trans or cis imidazo-
lidinones by Seebach’s method was solely applied to the
R-amino N-methyl amides as substrates, and other substitu-
tion (such as N-aryl) on the amide nitrogen atom was not
reported.3,4 Therefore, the utilization of Seebach’s principle
to synthesize R-substituted amino N-aryl amide 2 (Scheme
1) for BIRT-377 (1) is intriguing in relation to the possible
stereochemical outcome.
The synthesis of BIRT-377 (1) is outlined in Scheme 2.
The commercially available D-N-Boc-alanine (4) reacted with
3,5-dichloroaniline via a mixed anhydride intermediate
(i-BuOCOCl, N-methylmorpholine, -10 °C to rt, THF) to
give amide 5. Deprotection of the crude amide 5 by TFA in
dichloromethane afforded amino N-aryl amide 6 in 92% yield
over two steps. This crude product was pure enough to carry
on to next step without any purification.
In early laboratory studies, amino amide 6 was treated with
pivalaldehyde in refluxing pentane in a manner similar to
that described in Seebach’s original procedure. A crystalline
solid was directly formed from the reaction mixture and
identified as the desired trans imidazolidinone 716 as a single
diastereomer in 74% yield. This observation is in contrast
with Seebach’s case for the corresponding amino acid
N-methyl amide. Seebach reported that the acyclic Schiff
base intermediate was actually obtained in this step and then
cyclized only when treated with either HCl in MeOH at 0
°C or (PhCO)2O at 130 °C to generate stereoselectively either
trans or cis imidazolidinones in 90% ds and 71% ds,
respectively.5 Later (Scheme 3), it was found that a mixture
of trans/cis imidazolidinone 7/12 and Schiff base 11,
produced by treating amino amide 6 with pivalaldehyde in
toluene or dichloromethane, was completely converted to the
pure trans isomer 7 as a crystalline solid either when the
neat mixture stood over a period of time, or when the mixture
(3) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998,
9, 3517.
(4) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708.
(5) Naef, R.; Seebach, D. HelV. Chim. Acta 1985, 68, 135.
(6) Seebach, D.; Aehi, J. D.; Naef, R.; Weber, T. HelV. Chim. Acta 1985,
68, 144.
(7) Aehi, J. D.; Seebach, D. HelV. Chim. Acta 1985, 68, 1507.
(8) Seebach, D.; Dziadulewicz, E.; Behrendt, L.; Cantoreggi, S.; Fitzi,
R. Liebigs Ann. Chem. 1989, 1215.
(9) Grozinger, K. G.; Kriwacki, R. W.; Leonard, S. F.; Pitner, T. P. J.
Org. Chem. 1993, 58, 709.
(10) Seebach, D.; Gees, T.; Schuler, F. Liebigs Ann. Chem. 1993, 785.
(11) Kazmierski, W. M.; Urbanczyk-Lipkowska, Z.; Hruby, V. J. J. Org.
Chem. 1994, 59, 1789.
(12) Studer, A.; Seebach, D. Liebigs Ann. Chem. 1995, 217.
(13) Ma, D.; Tian, H. J. Chem. Soc., Perkin Trans. 1 1997, 3493.
(14) Jaun, B.; Tanaka, M.; Seiler, P,; Kuehnle, F. N. M.; Braun, C.;
Seebach, D. Liebigs Ann. Chem. 1997, 1697.
(15) Damhaut, P.; Lemaire, C.; Plenevaux, A.; Brihaye, C.; Christiaens,
L.; Comar, D. Tetrahedron 1997, 53, 5785.
(16) The corresponding cis isomer of 8 was independently prepared by
deprotonation of trans 8 with LiN(TMS)2 at 0 °C followed by quenching
the enolate with saturated aqueous NH4Cl at the same temperature. The
trans/cis stereochemistry was determined by NOESY experiment. The
chemical shifts for the N,N-acetal methine protons at the C-3 position in
trans and cis 8 are characteristically different: δ 6.39 ppm (for trans isomer);
δ 6.20 ppm (for cis isomer).
2782
Org. Lett., Vol. 2, No. 18, 2000