Synthesis of hydantoins from enantiomerically pure α-amino amides without epimerization

Article abstract of DOI:10.1021/jo052474s

A method for the preparation of enantiomerically pure hydantoins from optically pure α-amino amides utilizing triphosgene is described. We also propose that the racemization observed with 1,1′-carbonyldiimidazole (CDI) for this type of reaction is due to

Full text of DOI:10.1021/jo052474s

SCHEME 1
Synthesis of Hydantoins from Enantiomerically
Pure r-Amino Amides without Epimerization
Dun Zhang,† Xuechao Xing,‡ and Gregory D. Cuny*,‡
Department of Chemical & Biological Engineering, Tufts
UniVersity, Science and Technology Center, 4 Colby Street,
Medford, Massachusetts 02155, and Laboratory for Drug
DiscoVery in Neurodegeneration, Brigham & Women’s Hospital
and HarVard Medical School, 65 Landsdowne Street,
Cambridge, Massachusetts 02139
carbonyldiimidazole (CDI) were made (Scheme 1).6 Although
cyclization did proceed as expected, complete racemization was
observed.7,8 Bis(4-nitrophenyl)carbonate9 and 4-nitrophenyl
chloroformate10 have been reportedly employed in place of CDI
for this type of transformation with good stereochemical
integrity. However, some difficulty can be realized in the
separation of the desired hydantoin products from the byproduct,
4-nitrophenol. Nowick and co-workers reported that when
peptides were subjected to treatment with a toluene solution of
phosgene and pyridine in dichloromethane (DCM) peptide
isocyanates were produced along with variable quantities
(∼20%) of the corresponding hydantoins.11 Utilizing modified
Schotten-Baumann conditions, they were able to minimize the
production of hydantoins in favor of the peptide isocyanates.
Herein, we report methodology for the conversion of enantio-
merically pure R-amino amides to hydantoins without epimer-
ization.
gcuny@rics.bwh.harVard.edu
ReceiVed NoVember 30, 2005
A method for the preparation of enantiomerically pure
hydantoins from optically pure R-amino amides utilizing
triphosgene is described. We also propose that the racem-
ization observed with 1,1′-carbonyldiimidazole (CDI) for this
type of reaction is due to the imidazole carbamate intermedi-
ates.
Initially, we suspected that the presence of base (Et3N) was
responsible for the observed racemization. However, when the
reaction was conducted with CDI in the absence of base some
racemization still occurred, reducing the enantiomeric excess
to 70% (Table 1, entry 2). In addition, the reaction was sluggish
and only gave the hydantoin product in 50% yield. Next, we
sought an alternative coupling reagent for CDI. Triphosgene, a
useful substitute to phosgene, was selected.12 Gratifyingly, this
coupling reagent resulted in cyclization of 4 to give enantio-
merically pure hydantoin 5 (entries 3-5).13 Utilization of 0.4
equiv of triphosgene was optimum. Several bases were also
Hydantoins1 are an important structural moiety found in
several natural products, including (-)-deltoin, 1,2 and mid-
pacamide, 2,3 as well as many biologically active and thera-
peutically useful compounds, such as phenytoin, 3, utilized for
the treatment of seizures.4 In addition, hydantoins can serve as
useful intermediates in the synthesis of amino acids employing
hydantoinases and other related biocatalysts.5
(6) (a) Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino, J.
A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen, R.;
Carver, G.; Carella, A.; Holmes, K.; Lineberger, J.; Schleif, W. A.; Emini,
E. A. Bioorg. Med. Chem. Lett. 2001, 11, 3099-3102. (b) de Laszlo, S.
E.; Allen, E. E.; Li, B.; Ondeyka, D.; Rivero, R.; Malkowitz, L.; Molineaux,
C.; Siciliano, S. J.; Springer, M. S.; Greenlee, W. J.; Mantlo, N. Bioorg.
Med. Chem. Lett. 1997, 7, 213-218. (c) Lewis, R. T.; Macleod, A. M.;
Merchant, K. J.; Kelleher, F.; Sanderson, I.; Herbert, R. H.; Cascieri, M.
A.; Sadowski, S.; Ball, R. G.; Hoogsteen, K. J. Med. Chem. 1995, 38, 923-
933.
(7) (a) Nefzi, A.; Giulianotti, M.; Truong, L.; Rattan, S.; Ostresh, J. M.;
Houghten, R. A. J. Comb. Chem. 2002, 4, 175-178. (b) Nomoto, Y.; Takai,
H.; Hirata, T.; Teranishi, M.; Ohno, T.; Kubo, K. Chem. Pharm. Bull. 1990,
38, 3014-3019.
(8) For a recent example of a solid-phase method for the preparation of
enantiomerically pure hydantoins utilizing CDI, see: Va´zquez, J.; Royo,
M.; Albericio, F. Lett. Org. Chem. 2004, 1, 224-226.
Recently, in the course of conducting a structure-activity
relationship (SAR) study, attempts to prepare hydantoin (S)-5
by cyclizing R-amino amide 4 in the presence of 1,1′-
† Tufts University.
‡ Brigham & Women’s Hospital and Harvard Medical School.
(1) For a recent review of hydantoin chemistry, see: Meusel, M.;
Gu¨tschow, M. Org. Prep. Proced. Int. 2004, 36, 391-443.
(2) Chen, I.-S.; Chang, C.-T.; Sheen W.-S.; Teng, C.-M.; Tsai, I.-L.;
Duh, C. Y.; Ko, F. N. Phytochemistry 1996, 41, 525-530.
(3) (a) Jimenez, C.; Crews, P. Tetrahedron Lett. 1994, 35, 1375-1378.
(b) Fathi-Afshar, R.; Allen, T. M. Can J. Chem. 1988, 66, 45-50. (c)
Chevolot, L.; Padua, S.; Ravi, B. N.; Blyth, P. C.; Scheuer, P. J. Heterocycles
1977, 7, 891-894.
(9) Izdebski, J.; Pawlak, D. Pol. J. Chem. 1997, 71, 1066-1074.
(10) (a) Yamaguchi, J.; Harada, M.; Kondo, T.; Noda, T.; Suyama, T.
Chem Lett. 2003, 32, 372-373. (b) Itoh, F.; Nishikimi, Y.; Hasuoka, A.;
Yoshioka, Y.; Yukishige, K.; Tanida, S.; Aono, T. Chem. Pharm. Bull.
1998, 46, 255-273.
(11) Nowick, J. S.; Holmes, D. L.; Noronha, G.; Smith, E. M.; Nguyen,
T. M.; Huang, S.-L. J. Org. Chem. 1996, 61, 3929-3934.
(12) Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl. 1987, 26, 894-
895.
(4) McNamara, J. O. In Goodman & Gilman’s The Pharmacological
Basis of Therapeutics, Tenth Edition; Hardman, J. G., Limbird, L. E., Eds.;
McGraw-Hill: New York, 2001; Chapter 21, pp 528-531.
(5) Altenbuchner, J.; Siemann-Herzberg, M.; Syldatk, C. Curr. Opin.
Biotechnol. 2001, 12, 559-563.
(13) The enantiomeric excess of the products were determined by 1H
NMR spectroscopy using the chiral shift reagent Pr(hfc)3. This method could
accurately measuring 2% of the minor isomer.
10.1021/jo052474s CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/27/2006
1750
J. Org. Chem. 2006, 71, 1750-1753

TABLE 1. Effect of Reagents on the Formation of Hydantoin 514a
from r-Amino Amide 4
SCHEME 2
entry
reagent
base
Et3N
yield, %
ee, %
1
2
3
4
5
CDIa
55-75
50
30
42
71
0
70
>96
>96
>96
CDIa
triphosgeneb
triphosgeneb
triphosgeneb
Et3N
imidazole
pyridine
a CDI (10 equiv), CH2Cl2, Ar atm, 0 °C to rt for 13.5 h. b Triphosgene
(0.4 equiv), CH2Cl2, Ar atm, 0 °C for 1.5 h then 40 °C for 12 h.
isocyanates.16 Intermediates similar to 1011,17 and amino acid
ester isocyanates16b have been shown to be stable from race-
mization in the presence of base. Finally, cyclization of 9 and
11 gives the observed hydantoins (()-5 and (S)-5, respectively.
The intermediate imidazole carbamate 8 is therefore responsible
for the observed racemization seen with CDI resulting in (()-
5.
TABLE 2. Preparation of Hydantoins 7 from r-Amino Amides 6a
In summary, method for the preparation of enantiomerically
pure hydantoins from optically pure R-amino amides utilizing
triphosgene was developed. We also propose that the racem-
ization observed with CDI in this type of reaction is due to the
imidazole carbamate intermediates.
yield,
%
ee,
%
entry
R1
PhCH2
PhCH2
PhCH2
PhCH2
(CH3)2CHCH2 CH2Ph
TBSOCH2
PhCH2
R2
CH2CH3
(CH2)3CH3
CH2Ph
product
1
2
3
4
5
6
7
(S)-7a15b
(S)-7b
73
70
58
41
55
73
80
>96
>96
>96
>96
>96
>96
c
(S)-7c15c
(CH2)2-p-OMe-Ph (R)-7d
Experimental Section
(S)-7e
(R)-7f
(S,S)-7g
CH2Ph
General Procedure for the Preparation of R-Amino Amides
4 and 6a-c,e. A solution of the amino acid methyl ester
hydrochlorides (2 mmol) and the alkylamines (20 mmol) in
anhydrous methanol (10 mL) was stirred at room temperature for
3 days. The reaction mixture was concentrated, and the residue
was purified by column chromatography on silica gel using ethyl
acetate/methanol (96:4) as eluant to give the R-amino amides 4,
6a-c,e.
a Triphosgene (0.4 equiv), CH2Cl2, Ar atm, 0 °C for 1.5 h then 40 °C
for 12 h. b HCl salt of 6g was used. c de > 96%.
(S)-2-Amino-N-methyl-3-phenylpropionamide (4).18a 1H NMR
(500 MHz, CDCl3): δ 7.32 (t, 2H, J ) 7.5 Hz), 7.27-7.22 (m,
4H), 3.61 (dd, 1H, J ) 4.0, 9.5 Hz), 3.30 (dd, 1H, J ) 4.0, 13.5
Hz), 2.83 (d, 3H, J ) 7.5 Hz), 2.67 (dd, 1H, J ) 9.5, 13.5 Hz),
1.38 (brs, 2H).
evaluated in this reaction with pyridine proving best. Finally,
the highest yields were obtained when the reaction mixture was
initially stirred at 0 °C for 1.5 h and then at 40 °C for 12 h.
The scope of the reaction was evaluated utilizing a variety
of R-amino amides 6 (Table 2). These substrates were generally
prepared directly from the corresponding amino acid methyl
esters. In the case of (R)-6d, (R)-N-BOC-phenylalanine methyl
ester was allowed to react with 2-(4-methoxyphenyl)ethylamine
followed by removal of the BOC protecting group with
trifluoroacetic acid in DCM. Also, (R)-6f was prepared from
D-serine methyl ester by first protecting the alcohol with tert-
butyldimethylsilyl chloride and imidazole in DMF followed by
treatment with benzylamine in methanol. Cyclization of the
R-amino amides 6 with triphosgene (0.4 equiv) in the presence
of pyridine gave hydantoins 7 in moderate isolated yields (41-
80%) and in excellent optical purities (>96% ee).14
(S)-2-Amino-N-ethyl-3-phenylpropionamide (6a).18b 1H NMR
(500 MHz, CDCl3): δ 7.33 (t, 2H, J ) 7.5 Hz), 7.27-7.22 (m,
4H), 3.61 (dd, 1H, J ) 4.0, 9.0 Hz), 3.33-3.27 (m, 3H), 2.69 (dd,
1H, J ) 9.0, 13.5 Hz), 1.56 (brs, 2H), 2.67 (t, 3H, J ) 7.5 Hz).
(S)-2-Amino-N-butyl-3-phenylpropionamide (6b).18c 1H NMR
(500 MHz, CDCl3): δ 7.32 (t, 2H, J ) 7.0 Hz), 7.26-7.22 (m,
4H), 3.60 (dd, 1H, J ) 4.5, 9.5 Hz), 3.29-3.23 (m, 3H), 2.70 (dd,
1H, J ) 9.5, 13.5 Hz), 1.50-1.29 (m, 6H), 0.92 (t, 3H, J ) 7.5
Hz).
(S)-2-Amino-N-benzyl-3-phenylpropionamide (6c).18d 1H NMR
(500 MHz, CDCl3): δ 7.52 (s, 1H), 7.34-7.21 (m, 10H), 4.44 (m,
2H), 3.70 (dd, 1H, J ) 4.5, 9.5 Hz), 3.29 (dd, 1H, J ) 4.5, 13.5
Hz), 2.70 (dd, 1H, J ) 9.5, 13.5 Hz), 1.70 (brs, 2H).
Treatment of 4 with CDI or triphosgene/base presumably
gives intermediates 8 and 10, respectively (Scheme 2). These
intermediates can proceed to generate isocyanates. Both reagents
have previously been utilized to produce isolable aliphatic
(16) (a) Takeda, Y.; Kawagoe, K.; Yokomizo, A.; Yokomizo, Y.;
Hosokami, T.; Ogihara, Y.; Yokohama, S. Chem. Pharm. Bull. 1998, 46,
434-444. (b) Nowick, J. S.; Powell, N. A.; Ngugen, T. M.; Noronha, G. J.
Org. Chem. 1992, 57, 7364-7366.
(17) Chong, P. Y.; Petillo, P. A. Tetrahedron Lett. 1999, 40, 2493-
2496.
(14) Cyclization of 6c with CDI in CH2Cl2 gave racemic 7c. Cyclization
of 6g (HCl salt) with CDI in DMF in the presence of DIPEA gave 7g as a
mixture of diastereomers resulting from epimerzation of the hydantoin.
(15) (a) Lazarus, R. A. J. Org. Chem. 1990, 55 (15), 4755-4757. (b)
Wolfe, S.; Bowers, R. J.; Shin, H. S.; Sohn, C. K.; Weaver, D. F.; Yang,
k. Can. J. Chem. 1988, 66, 2751-2762. (c) Zhai, Z.; Chen, J.; Wang, H.;
Zhang, Q. Synth. Commun. 2003, 33 (11), 1873-1883.
(18) (a) Ojima, I.; Chen, H. J. C.; Qiu, X. G. Tetrahedron 1988, 44,
5307-5718. (b) Suzuki, K.; Fujita, H.; Sasaki, Y.; Shiratori, M.; Sakurada,
S.; Kisara, K. Chem. Pharm. Bull. 1988, 36, 4834-4840. (c) Degrado, S.
J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 755-756.
(d) Conley, J. D.; Kohn, H. J. Med. Chem. 1987, 30, 567-574. (e) Evans,
B. E.; Rittle, K. E.; Homnick, C. F.; Springer, J. P.; Hirshfield, J.; Veber,
D. F. J. Org. Chem. 1985, 50, 4615-4625.
J. Org. Chem, Vol. 71, No. 4, 2006 1751

(S)-2-Amino-4-methylpentanoic Acid Benzylamide (6e).18e 1
H
MgSO4, filtered, and concentrated. The residue was purified by
column chromatography on silica gel using DCM/ethyl acetate (80:
20) to afford the hydantoins 7.
(S)-5-Benzyl-3-methylimidazolidine-2,4-dione (5).15a 1H NMR
(400 MHz, CDCl3): δ 7.35-7.29 (m, 3H), 7.20 (d, 2H, J ) 6.8
Hz), 5.18 (brs, 1H), 4.23 (ddd, 1H, J ) 1.2, 3.6, 10.0 Hz), 3.33
(dd, 1H, J ) 3.6, 14.0 Hz), 2.99 (s, 3H), 2.79 (dd, 1H, J ) 10.0,
14.0 Hz). [R]22.3D ) -86.5 (c 1.0, acetone) [lit.15a [R]24D ) -113.0
(c 1.0, acetone)].
NMR (500 MHz, CDCl3): δ 7.62 (s, 1H), 7.33 (t, 2H, J ) 7.0
Hz), 7.29-7.26 (m, 3H), 4.45 (d, 2H, J ) 6.0 Hz), 3.45 (dd, 1H,
J ) 4.0, 10.0 Hz), 1.80-1.73 (m, 2H), 1.56 (brs, 2H), 1.38 (m,
1H), 0.97 (d, 3H, J ) 7.0 Hz), 0.94 (d, 3H, J ) 6.0 Hz).
(R)-2-Amino-N-[2-(4-methoxyphenyl)ethyl]-3-phenylpropi-
onamide (6d). A solution of (R)-N-BOC-phenylalanine methyl ester
(0.43 g, 1.54 mmol) and 2-(4-methoxy phenyl)ethylamine (1.5 g,
10 mmol) in anhydrous methanol (5 mL) was stirred at room
temperature for 3 d. After removal of the solvent, the residue was
purified by column chromatography on silica gel using hexane/
ethyl acetate (70:30) as eluant to give (R)-2-N-BOC-amino-N-[2-
(4-methoxyphenyl)ethyl]-3-phenylpropionamide as a light yellow
solid (325 mg, 53%).: 1H NMR (500 MHz, CDCl3): δ 7.30 (t,
2H, J ) 7.5 Hz), 7.25 (m, 1H), 7.18 (d, 2H, J ) 7.0 Hz), 6.93 (d,
2H, J ) 8.5 Hz), 6.79 (d, 2H, J ) 8.0 Hz), 5.62 (brs, 1H), 5.01
(brs, 1H), 4.23 (brs, 1H), 3.78 (s, 3H), 3.42-3.30 (m, 2H), 3.10-
2.95 (m, 2H), 2.67-2.50 (m, 2H), 1.40 (s, 9H). 13C NMR (100.5
MHz, CDCl3): δ 171.1, 158.5, 130.7, 129.8, 129.6, 128.9, 127.2,
(S)-5-Benzyl-3-ethylimidazolidine-2,4-dione (7a).15b 1H NMR
(500 MHz, CDCl3): δ 7.35-7.28 (m, 3H), 7.20 (d, 2H, J ) 7.0
Hz), 5.12 (brs, 1H), 4.22 (ddd, 1H, J ) 1.5, 4.0, 9.0 Hz), 3.51 (m,
2H), 3.28 (dd, 1H, J ) 4.0, 14.0 Hz), 2.79 (dd, 1H, J ) 10.0, 14.0
Hz), 1.11 (t, 3H, J ) 7.5 Hz). [R]24.5 ) -92.4 (c 0.5, MeOH).
D
(S)-5-Benzyl-3-butylimidazolidine-2,4-dione (7b). 1H NMR
(500 MHz, CDCl3): δ 7.35-7.18 (m, 5H), 5.15 (brs, 1H), 4.22
(ddd, 1H, J ) 1.0, 4.0, 9.0 Hz), 3.43-3.36 (m, 2H), 3.27 (dd, 1H,
J ) 4.0, 14.5 Hz), 2.84 (dd, 1H, J ) 9.0, 14.5 Hz), 1.52-1.45 (m,
2H), 1.28-1.18 (m, 2H), 0.89 (t, 3H, J ) 7.5 Hz). 13C NMR (100.5
MHz, CDCl3): 173.3, 157.3, 135.4, 129.5, 129.1, 127.7, 58.4, 38.6,
38.2, 30.2, 20.1, 13.8. Mp: 136-137 °C. [R]24.2D ) -86.0 (c 0.5,
MeOH). FT-IR (KBr pellet, νmax, cm-1): 3315brs, 2952s, 2868m,
1753s, 1708s, 1693s, 1456s, 1426s, 1186m, 1096m, 759m, 707s,
616m. HRESMS [M + H]+: 247.1449 (calcd for [C14H18N2O2 +
H]+, 247.1446).
114.3, 55.5, 41.0, 39.0, 34.8, 28.5. Mp: 139-140 °C. [R]24.3
)
D
-1.6 (c 0.5, MeOH). FT-IR (KBr pellet, νmax, cm-1): 3348s, 3323s,
2971m, 2827m, 1686s, 1652s, 1548s, 1514s, 1246s, 1169s, 1031m,
820m, 765m, 703m. HRESMS [M + H]+: 399.2286 (calcd for
[C23H30N2O4 + H]+, 399.2284).
Next, a solution of (R)-2-N-BOC-amino-N-[2-(4-methoxyphen-
yl)ethyl]-3-phenylpropionamide (398 mg, 1 mmol) and trifluoro-
acetic acid (1.14 g, 10 mmol) in anhydrous DCM (2 mL) was stirred
at room temperature for 1 h. After removal of the solvent, the
residue was partitioned between ethyl acetate and saturated
NaHCO3. The organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated to give 6d as a pale yellow oil (268 mg,
(S)-5-Benzyl-3-benzylimidazolidine-2,4-dione (7c).15c 1H NMR
(500 MHz, CDCl3): δ 7.31-7.26 (m, 8H), 7.17-7.15 (m, 2H),
5.32 (brs, 1H), 4.63 (d, 1H, J ) 14.5 Hz), 4.58 (d, 1H, J ) 14.5
Hz), 4.25 (ddd, 1H, J ) 1.5, 4.0, 9.0 Hz), 3.27 (dd, 1H, J ) 4.0,
14.0 Hz), 2.79 (dd, 1H, J ) 9.0, 14.0 Hz). [R]24.5D ) -62.8 (c 0.5,
MeOH).
1
90%). H NMR (500 MHz, CDCl3): δ 7.32 (t, 2H, J ) 7.5 Hz),
(R)-5-Benzyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidine-2,4-
1
7.25-7.19 (m, 3H), 7.06 (d, 2H, J ) 8.0 Hz), 6.83 (d, 2H, J ) 9.0
Hz), 3.79 (s, 3H), 3.61 (dd, 1H, J ) 4.5, 8.5 Hz), 3.53-3.41 (m,
2H), 3.24 (dd, 1H, J ) 4.5, 13.5 Hz), 2.73 (t, 2H, J ) 8.5 Hz),
2.70 (dd, 1H, J ) 9.5, 13.5 Hz). 13C NMR (100.5 MHz, CDCl3):
δ 174.3, 158.4, 138.2, 131.2, 129.9, 129.5, 128.9, 127.0, 114.2,
dione (7d). H NMR (500 MHz, CDCl3): δ 7.33 (t, 2H, J ) 8.0
Hz), 7.27 (t, 1H, J ) 8.0 Hz), 7.18 (d, 2H, J ) 7.0 Hz), 7.12 (d,
2H, J ) 7.0 Hz), 6.83 (d, 2H, J ) 8.0 Hz), 5.08 (brs, 1H), 4.15
(ddd, 1H, J ) 1.0, 2.5, 7.5 Hz), 3.78 (s, 3H), 3.69 (ddd, 1H, J )
6.5, 8.5, 13.5 Hz), 3.65 (ddd, 1H, J ) 6.5, 8.5, 14.0 Hz), 3.23 (dd,
1H, J ) 4.0, 9.0 Hz), 2.79 (ddd, 2H, J ) 2.5, 5.2, 8.0 Hz), 2.68
(dd, 1H, J ) 9.5, 14.0 Hz). 13C NMR (100.5 MHz, CDCl3): δ
173.0, 158.6, 156.9, 135.6, 130.1, 130.0, 129.4, 129.2, 127.7, 114.2,
58.4, 55.5, 40.1, 38.3, 33.1. Mp: 149-150 °C. [R]24.6D ) +122.4
(c 0.5, MeOH). FT-IR (KBr pellet, νmax, cm-1): 3288brs, 2936m,
2837m, 1755s, 1705s, 1696s, 1513s, 1461s, 1241s, 1176m, 1033m,
753m, 703m, 628m. HRESMS [M + H]+: 325.1561 (calcd for
[C19H20N2O3 + H]+, 325.1552).
56.7, 55.5, 41.3, 40.6, 35.1. [R]24.6 ) +1.2 (c 0.5, MeOH).
D
HRESMS [M + H]+: 299.1755 (calcd for [C18H22N2O2 + H]+,
299.1759).
(R)-2-Amino-N-benzyl-3-(tert-butyldimethylsilanylloxy)pro-
pionamide (6f). To a solution of d-serine methyl ester (1.19 g, 10
mmol) in DCM (40 mL) at 0 °C was added tert-butyldimethylsilyl
chloride (3.16 g, 21 mmol) followed by imidazole (slowly). The
mixture was allowed to warm to room temperature and stirred
overnight. It was then poured into water (20 mL). The aqueous
layer was washed with DCM (20 mL × 3). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concentrated
to give (R)-2-amino-3-(tert-butyldimethylsilanylloxy)propionic acid
methyl ester. This material was used without further purification
and converted to 6f followed the general procedure outlined for
(S)-3-Benzyl-5-isobutylimidazolidine-2,4-dione (7e). 1H NMR
(500 MHz, CDCl3): δ 7.41-7.25 (m, 5H), 5.35 (s, 1H), 4.68 (d,
1H, J ) 18.5 Hz), 4.63 (d, 1H, J ) 18.5 Hz), 4.04 (dd, 1H, J )
3.0, 12.5 Hz), 1.85-1.70 (m, 2H), 1.59-1.47 (m, 1H), 0.96 (d,
3H, J ) 3.0 Hz), 0.95 (d, 3H, J ) 2.5 Hz). 13C NMR (100.5 MHz,
CDCl3): δ 174.3, 157.3, 136.2, 128.9, 128.8, 128.1, 56.1, 42.4,
1
41.1, 25.5, 23.2, 21.8. Mp: 79-80 °C. [R]24.2 ) -55.2 (c 0.5,
the preparation of R-amino amides 4 and 6a-c,e. H NMR (500
D
MeOH). FT-IR (KBr pellet, νmax, cm-1): 3238brs, 2959s, 2875m,
1767s, 1712s, 1450s, 1350s, 1198m, 1079m, 748m, 692s, 630m;
HRESMS [M + H]+: 247.1451 (calcd for [C14H18N2O2 + H]+,
247.1446).
MHz, CDCl3): δ 7.73 (brs,1H), 7.35-7.24 (m, 5H), 4.48 (dd, 1H,
J ) 6.0, 14.5 Hz), 4.42 (dd, 1H, J ) 5.5, 14.5 Hz), 3.87 (dd, 1H,
J ) 6.0, 10.0 Hz), 3.82 (dd, 1H, J ) 4.0, 10.0 Hz), 3.49 (t, 1H, J
) 5.5 Hz), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). 13C NMR (100.5
MHz, CDCl3): δ 173.0, 138.6, 128.8, 127.9, 127.6, 65.5, 56.8, 43.4,
26.0, 18.4, -5.2. [R]24.6D ) -4.0 (c 0.5, MeOH). HRESMS [M +
H]+: 309.1992 (calcd for [C16H28N2O2Si + H]+, 309.1998).
(R)-3-Benzyl-5-(tert-butyldimethylsilanyloxymethyl)imid-
azolidine-2,4-dione (7f). 1H NMR (500 MHz, CDCl3): δ 7.39 (d,
2H, J ) 6.5 Hz), 7.31 (t, 2H, J ) 6.5 Hz), 7.27 (d, 1H, J ) 7.0
Hz), 5.31 (brs, 1H), 4.66 (d, 1H, J ) 14.5 Hz), 4.63 (d, 1H, J )
14.5 Hz), 4.10 (dd, 1H, J ) 3.5, 6.0 Hz), 3.92 (dd, 1H, J ) 3.5,
11.0 Hz), 3.84 (dd, 1H, J ) 6.0, 11.0 Hz), 0.83 (s, 9H), 0.03 (s,
3H), 0.02 (s, 3H). 13C NMR (100.5 MHz, CDCl3): δ 171.7, 157.6,
136.1, 128.9, 128.8, 128.1, 62.7, 59.7, 42.4, 25.9, 18.4, -5.31,
General Procedure for the Preparation of Hydantoins 7 from
Amino Amides 6. A solution of 6 (0.3 mmol) and pyridine (0.4
mL) in 3 mL of anhydrous DCM under an Ar atmosphere was
cooled to 0 °C. A solution of triphosgene (36 mg, 0.12 mmol) in
DCM (2 mL) was added. The resulting mixture was stirred at 0 °C
for 1.5 h and then at 40 °C for 12 h. The reaction mixture was
allowed to cool to room temperature, DCM (10 mL) and 1 N HCl
(3 mL) were added. The aqueous layer was washed with DCM (10
mL × 3). The combined organic layers were dried over anhydrous
-5.34. Mp: 128-129 °C. [R]24.0 ) +58.8 (c 0.5, MeOH). FT-
D
IR (KBr pellet, νmax, cm-1): 3333brs, 2954s, 2928s, 2856s, 1764s,
1707s, 1449s, 1425s, 1126s, 984m, 777s, 714m, 624m. HRESMS
[M + H]+: 335.1796 (calcd for [C17H26N2O3Si + H]+, 335.1791).
1752 J. Org. Chem., Vol. 71, No. 4, 2006

[2S(4S)]-2-(4-Benzyl-2,5-dioxoimidazolidin-1-yl)-3-phenylpro-
pionic Acid Methyl Ester (7g). To N-Boc-L-phenylalanyl-L-
phenylalanine methyl ester19 (85 mg, 0.2 mmol) in methanol (1
mL) at 0 °C was added acetyl chloride (0.4 mL) under argon. The
mixture was stirred at room temperature for 2 h. Concentration of
the mixture gave a white solid (HCl salt), which was used without
further purification following the general procedure for converting
6 to 7. 1H NMR (500 MHz, CDCl3): δ 7.33-7.25 (m, 5H), 7.21-
7.24 (m, 3H), 7.11-7.10 (m, 2H), 5.05 (s, 1H), 4.98 (dd, 1H, J )
10.5, 6.5 Hz), 4.06 (ddd, 1H, J ) 11.0, 3.5, 1.0 Hz), 3.80 (s, 3H),
3.48-3.50 (m, 2H), 3.07 (dd, 1H, J ) 13.5, 3.5 Hz), 2.12 (dd, 1H,
J ) 13.5, 11.0 Hz). 13C NMR (100.5 MHz, CDCl3): δ 172.5, 169.2,
155.8, 136.7, 135.9, 129.4, 129.3, 129.2, 128.8, 127.7, 127.3, 58.4,
53.4, 53.1, 38.4, 34.3. Mp: 184-185 °C. [R]21.4 ) -207.8 (c
D
1.0, acetone). FT-IR (KBr pellet, νmax, cm-1): 3296brs, 3029m,
2924m, 1761s, 1710s, 1426s, 1361s, 1246s, 1048m, 763m, 720m,
582m. Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95.
Found: C, 68.07; H, 5.26; N, 7.95.
Acknowledgment. We appreciate financial support from the
Harvard Center for Neurodegeneration and Repair (HCNR).
Supporting Information Available: 1H and/or 13C NMR
spectra for 4, 5, 6a-f, and 7a-g. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) Donkor, I. O.; Sanders, M. L. Bioorg. Med. Chem. Lett. 2001, 11,
2647-2649.
JO052474S
J. Org. Chem, Vol. 71, No. 4, 2006 1753