Asymmetric Synthesis of 4,4-Disubstituted-2-Imidazoli-dinones: Potent NK1 Antagonists

Article abstract of DOI:10.1021/ol030104p

(Equation presented) A highly efficient and practical synthesis of 4,4-Disubstituted-2-Imidazolidinones utilizing a "self-reproduction of the center of chirality" strategy is described.

Full text of DOI:10.1021/ol030104p

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4249-4251
Asymmetric Synthesis of
4,4-Disubstituted-2-Imidazoli-dinones:
Potent NK1 Antagonists
Gregory A. Reichard,†,‡ Carmine Stengone,‡ Sunil Paliwal,‡ Ingrid Mergelsberg,§
Sapna Majmundar,‡ Cheng Wang,‡ Robert Tiberi,‡ Andrew T. McPhail,|
,‡
John J. Piwinski,‡ and Neng-Yang Shih*
Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, New Jersey 07033, Werthenstein Chemie AG, Industriestrasse,
CH-6105 Schachen, Switzerland, and Department of Chemistry, P.M. Gross Chemical
Laboratory, Duke UniVersity, Durham, North Carolina 27708
neng-yang.shih@spcorp.com
Received August 25, 2003
ABSTRACT
A highly efficient and practical synthesis of 4,4-Disubstituted-2-Imidazolidinones utilizing a “self-reproduction of the center of chirality” strategy
is described.
We have recently disclosed a series of 4,4-disubstituted-2-
imidazolidinones as potent NK1 antagonists.1 To perform a
comparative analysis of our most promising compounds in
this class, multigram quantities of several analogues were
needed in optically pure form. To meet these material
requirements, a thorough investigation of various synthetic
methods toward an optically pure imidazolidinone core was
undertaken.
Numerous methods to resolve the hydantoin intermediate
or imidazolidinone product were surveyed, and a practical
chiral chromatographic method was discovered allowing
Scheme 1. Racemic Synthesis of 4,4-Disubstituted
2-Imidazolidinonesa
Initially, a practical racemic synthesis of the imidazolidi-
none ring was developed (Scheme 1). Alkylation of R-hy-
droxy acetophenone by treatment of the triflate of 3,5-
bis(trifluoromethyl)benzyl alcohol in the presence of 2,6-
di-tert-butyl-4-methyl pyridine was followed by subsequent
hydantoin formation under standard conditions. Reduction
with lithium aluminum hydride/aluminum trichloride pro-
vided the desired imidazolidinone.
† Current address: Department of Chemistry, Pfizer Global Research
and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105.
‡ Schering-Plough Research Institute.
a Reagents and conditions: (a) 3,5-bis(trifluoromethyl)benzyl
alcohol, 2,6-di-tert-butyl-4-methyl-pyridine, trifluoromethane sul-
fonic anhydride, CH2Cl2; (b) potassium cyanide, ammonium
carbonate, 50% aqueous ethanol; (c) lithium aluminum hydride,
aluminum trichloride, THF.
§ Werthenstein Chemie AG, Industriestrasse.
| Duke University.
(1) Shih, N.-Y.; Shue, H.-J.; Reichard, G. A.; Paliwal, S.; Blythin, D.
J.; Piwinski, J. J.; Xiao, D.; Chen, X. PCT Int. Appl. WO 0144200, 2001.
10.1021/ol030104p CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003

Scheme 2. Retrosynthetic Analysis: Asymmetric Route
Scheme 3. Alkylation of Imidazolidinone 13
access to multigram quantities of optically pure imidazoli-
dinone 4. Further structural changes around this lead
compound resulted in targets that could be separated via
chiral chromatography with varying degrees of success. To
circumvent chromatographic resolution procedures, a general
and practical asymmetric synthesis of 4,4-disubstituted
2-imidazolidinones was sought.
Thus, treatment of phenylglycine methyl ester 11 with an
aqueous solution of methylamine provided the amide 12 with
minimal epimerization.9 Treatment of the amino amide 12
with pivalaldehyde in pentane with azeotropic removal of
water followed by treatment with hydrochloric acid installs
the temporary tert-butyl stereocenter (trans/cis ratio of 6:1).
Neutralization of the amine hydrochloride salt with potassium
carbonate and isolation via aqueous workup provided the
crystalline free base imidazolidinone 13. Recrystallization
from MTBE removed the minor cis isomer to provide pure
13 in >99% ee as one diastereomer by 1HNMR with
excellent recovery.
Imidazolidinone 13 was alkylated with 1410 using LDA
/THF11 to provide the R,R-disubstituted phenylglycine de-
rivative 15 in >95:5 diastereomeric ratio with excellent
isolated yields in the range of 70-75%.12
Various bromomethyl ethers containing substitution at the
benzylic center were also employed for structure-activity
relationship investigation purposes (data not shown). The
most biologically interesting of these targets contained a
chiral benzylic methyl group.13 Preparation of the required
bromomethyl ether in quantity (Scheme 4) required a large
supply of (R)-R-methyl 3,5-bis(trifluoromethyl)benzyl alco-
Our approach (Scheme 2) is based on the “self reproduc-
tion of the center of chirality” method developed by D.
Seebach.2 The cyclic urea, 5, would be made from hydantoin
intermediate 6, which can readily be prepared from the R,R-
disubstituted phenylglycine amino acid 7. This amino acid
would result from hydrolytic opening of the imidazolidinone
8. Diastereoselective alkylation of the imidazolidinone 9
should occur with bottom face approach of the incoming aryl
bromomethyl ether. This bond disconnection represents an
efficient way of preparing the minimal pharmacophoric
elements (highlighted below) of phenylglycinol-based NK1
antagonists3 on fully substituted systems with the overall
absolute stereochemistry originating from phenylglycine.
The initial synthetic implementation of our strategy utilized
the N-benzoyl-protected imidazolidinone;4 however, we
encountered problems with the extreme conditions needed
to hydrolyze the benzoyl group of the dialkylated N-benzoyl-
imidazolidinones.5,6 To circumvent this problematic cleavage,
we sought to explore the “unprotected” imidazolidinone 13
(Scheme 3).7,8
(8) See: Seebach, D.; Aebi, J. D.; Naef, R.; Weber, T. HelV. Chim. Acta
1985, 68, 144.
(2) Seebach, D.; Imwinkelried, R.; Weber, T. Mod. Synth. Methods 1986,
129.
(3) Swain, C. J.; Cascieri, M. A.; Owens, A.; Saari, W.; Sadowski, S.;
Strader, C.; Teall, M.; Van Neal, M. B.; Williams, B. J. Bioorg. Med. Chem.
Lett. 1994, 4, 2161.
(4) Typically, the nitrogen of the imidazolidinone employed for Seebach’s
approach is functionalized as a carbamate or acyl derivative in order to
control the cis/trans ratio of the temporary stereocenter or confer crystallinity
for purification purposes.
(5) Hydrolytic cleavage of bulky disubstituted imidazolidinones can be
quite problematic, particularly for substituents larger than methyl on the
phenylglycine system (ref 6a,b). The structural requirements for our
compounds were not tolerant of these conditions.
(9) Standard amidation conditions utilizing a methanolic solution of
methylamine require long reaction times (>14 h) and epimerize the R-proton
resulting in the isolation of 12 in 70% ee. An alternative solution to this
racemization problem employs the coupling of N-Boc phenylglycine with
methylamine using HOOBT to provide N-Boc amino amide in >98% ee.
Standard deprotection conditions provide 12 in excellent yield.
(10) Prepared from treatment of a melt of paraformaldehyde and 3,5-
bis(trifluoromethyl)benzyl alcohol with gaseous hydrobromic acid.
(11) Deoxygenation of the solvent and reagents is critical for clean and
reproducible runs of the alkylation.
(12) Isolated yields after column chromatography. Generally, for large-
scale reactions, the product was purified by crystallization, which provided
15 in 50% isolated yield (see Experimental Section).
(13) Swain, C. J.; Williams, B. J.; Baker, R.; Cascieri, M. A.; Chicchi,
G.; Forrest, M.; Herbert, R.; Keown, L.; Ladduwahetty, T.; Luell, S.;
Macintyre, D. E.; Metzger, J.; Morton, S.; Owens, A. P.; Sadowski, S.;
Watt, A. P. Bioorg. Med. Chem. Lett. 1997, 7, 2959.
(6) (a) Studer, A.; Seebach, D. Liebigs Ann. 1995, 217. (b) Obrecht, D.;
Heimgartner, H. HelV. Chim. Acta 1981, 64, 482.
(7) Although the diastereoselective ethylation of imidazolidinone 13 has
been reported (see ref 8), we could find no characterization of imidazoli-
dinone 13 or any further reference of its use.
4250
Org. Lett., Vol. 5, No. 23, 2003

Scheme 4. Asymmetric Synthesis of 4,4-Disubstituted
2-Imidazolidinones
Figure 1. ORTEP representation of the crystal structure of 19.
required cyclic urea as before using LAH/AlCl3. Recrystal-
lization from hot MTBE provided the final product in >99%
ee as a single diastereomer.
Thus, the employment of crystalline imidazolidinone 13
resulted in the discovery of a highly efficient route to
optically pure 4,4-disubstituted 2-imidazolidinones. The
yields for the seven-step synthesis are generally very good;
the transformations can be carried out on very large scale,
and little chromatography is needed to provide 4,4-disub-
stituted 2-imidazolidinone NK1 antagonists in optically pure
form. A procedure for the amidation of stereochemically
labile phenylglycine esters with minimal racemization has
been established. Furthermore, the utility of employing
substituted benzylbromomethyl ether electrophiles to ste-
reoselectively install the NK1 pharmacophore in hindered
disubstituted systems has been discovered. The generality
of this key step with other core systems to give rise to novel
NK1 antagonists is the focus of current work and will be the
subject of future publications.
a Isolated yields of 19 in >95:5 diastereomeric ratio after column
chromatography.
hol (17). CBS reduction14 of 3,5-bis(trifluoromethyl)-ac-
etophenone (16) was optimized to provide over 300 g of
17. Treatment of a melt of paraformaldehyde and chiral
alcohol 17 with gaseous hydrobromic acid for 2 h followed
by anhydrous extractive workup with hexane and distillation
gave the bromomethyl ether 18 in >90% yield on scales of
>100 g.15
Imidazolidinone 13 was alkylated with 18 using LDA/
THF to afford the R,R-disubstituted phenylglycine derivative
19 in >95:5 diastereomeric ratio with isolated yields in the
range of 70-75%. Recrystallization of 19 from pentane
provided material that is diastereomerically and enantio-
merically pure in 55% isolated yield. The absolute config-
uration of 19 was confirmed by X-ray crystallographic
analysis (Figure 1).
Acknowledgment. The authors thank D. Blythin, H.-J.
Shue, X. Chen, J. Schwerdt, and D. Gu for their contributions
to the racemic synthesis and separation of the optical isomers
of 4 and its various analogues. Additionally, the authors thank
Dr. M. Wrobleski and Dr. C. Strickland for their help in
preparing the manuscript.
Subsequent treatment of 19 with methanolic/aqueous HCl
gave the desired amino amide 20 in >95% yield with no
need for chromatographic purification. The resulting amino
amide was then treated with chlorosulfonylisocyanate fol-
lowed by 25% aqueous HCl/dioxane to afford the desired
crystalline hydantoin. The hydantoin was reduced to the
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 12-20 and Sch
425078 and crystallographic details for compound 19 in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) For an excellent review, see: Corey, E. J.; Helal, C. J. Angew.
Chem., Int. Ed. 1998, 37, 1986.
(15) The % ee of 18, checked by hydrolysis back to the chiral alcohol
17 by treatment on silica gel, was found to be unchanged (95% ee) as a
result of the conditions required for bromomethyl ether formation.
OL030104P
Org. Lett., Vol. 5, No. 23, 2003
4251