Hydantoin formation by cyclo-elimination: Reactivity difference between Merrifield- and Wang-derived resins

Article abstract of DOI:10.1016/S0040-4039(00)01073-X

cyclo-Elimination reactivity differences in I→II are reported. These reactivity differences dictate the selection of Wang resin for N1-substituted hydantoin formation and Merrifield resin for N1-unsubstituted hydantoin formation. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01073-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7409–7413
Hydantoin formation by cyclo-elimination: reactivity
difference between Merrifield- and Wang-derived resins
Kyung-Ho Park and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616, USA
Received 14 June 2000; accepted 26 June 2000
Abstract
cyclo-Elimination reactivity differences in I“II are reported. These reactivity differences dictate the
selection of Wang resin for N1-substituted hydantoin formation and Merrifield resin for N1-unsubstituted
hydantoin formation. © 2000 Elsevier Science Ltd. All rights reserved.
Successful solid-phase chemistry requires careful selection of (i) the solid-support which must
be compatible with the synthetic transformations, (ii) the linker technology which must
accommodate the chemistry and yet liberate the final product with high efficiency, (iii) the
protecting group strategies employed which must be coordinated with target functionality and
reactivity, and (iv) the solvents employed which must effectively support both the chemistry and
the resin.1 Numerous studies have established that linkers which incorporate cyclo-elimination2
release strategies are particularly important in solid-phase organic synthesis in that only
cyclizable precursors are positioned for release, hence contributing to final product purity. Since
DeWitt et al.3 first reported production of an hydantoin library from Wang resin using an ester
linker with cyclo-elimination release, a number of related strategies for hydantoin production
have been reported. Of these, some protocols4 have employed Wang-based ester linkers (I®=W
;
=Wang), while others5 have employed Merrifield-based (I®=M
;
=Merrifield) ester linkers.
®
®
Given the widespread use of these two resins, it is surprising that there are no reports regarding
cyclo-elimination differences in these two ester-linked resins. We report here the discovery of
fundamental reactivity idiosyncrasies between these resins in I®=M/W“II; these reactivity
differences dramatically bias resin selection for library production.
R
O
R
O
O
H
N
H
N
N
N
=
=
®
®
O
R
NH
NH
®
O
O
M = Merrifield
W = Wang
O
I
II
II
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01073-X

7410
To compare the reactivity differences, allyl substituted N-protected amino ester 16 (3 g, 9.8
mmol scale; Scheme 1), an important precursor for the construction of hydantoin–isoxazoline
heterocycles, was hydrolyzed and subsequently Boc- or Fmoc-protected to afford 3 (72% overall
yield) or 5 (78% overall yield), respectively. This difference in N-protection reflects Boc-compat-
ibility with Merrifield resin and Fmoc-compatibility with Wang resin.
Scheme 1.
These protected amino acids were coupled with Merrifield (either DIC-mediated coupling of
3 or 18-crown-6-mediated coupling of the potassium salt of 3) and Wang (DIC-mediated
coupling of 5; Scheme 2) resin. After removal of the Boc or Fmoc protecting group, each amino
ester bound resin was treated with phenyl isocyanate to give urea 7®=M/W (urea FTIR at 1656
cm−1) and the cyclization to the final hydantoin was investigated. Without base, neither of these
resins released hydantoin 8. However, treating THF-swollen Merrifield resin 7®=M with Et3N at
gentle reflux (60°C, overnight) delivered 8 in 95% overall yield. Identical conditions with Wang
resin 7®=W gave no trace of 8.
+
3 (K salt)
O
18-crown-6
X = Cl
DMF
NH-PG
5
O
X
or
®
Cl
W = Wang
M
W
DIC, DMAP
DMF/DCM
X = OH
3
M = Merrifield
6
DIC, DMAP
DMF/DCM
i. 50% TFA and Et N (Merrifield)
3
or 20% piperidine (Wang)
ii. PhNCO
= M
®
no hydantoin
(8) formed
no Et3N
O
H
N
H
N
= W
®
no hydantoin
(8) formed
O
Ph
O
®
with or
O
N
without
= M
®
Et3N
NH
7
O
Et3N
8
Scheme 2.
Protocol for 7®=M“8: acid 3 (0.79 g, 3.68 mmol) and DIC (0.46 g, 3.68 mmol) were dissolved
in DMF/CH2Cl2 (2 mL/8 mL) and this solution was added to a flask containing hydroxy-

7411
methylene polystyrene resin (1.35 g, 0.92 mmol, 0.68 mmol/g). A solution of DMAP (45 mg,
0.37 mmol) in DMF/CH2Cl2 (2 mL/8 mL) was added and the reaction mixture was stirred
overnight at ambient temperature. The resin was washed with DMF, CH2Cl2, and ether, and
dried to give 6®=M (=Merrifield resin; PG=Boc). This resin was treated with 50% TFA in
DCM (10 mL) at rt for 1 h at which time the resin was washed with DMF, DCM, and 20%
Et3N in DCM (10 mL×5). The resulting DCM-swollen resin was treated with phenyl isocyanate
(0.44 g, 3.68 mmol) at rt for 10 h, washed with DMF, THF, and DCM, and dried to afford
Merrifield-derived resin 7®=M. This resin was treated with Et3N (0.37 g, 3.68 mmol) in THF (10
mL) at 60°C overnight. The combined solution from resin filtration and washing (THF) was
concentrated under reduced pressure and purified by a short silica-gel column to afford
hydantoin 8 (0.19 g, 0.87 mmol, 95% from Merrifield resin) as a solid.7
As outlined in Scheme 3, we next investigated hydantoin formation from polymer-bound
N1-substituted urea 11®=M/W. This N1-substituent was introduced by reductive N-alkylation of
amino resin 9®=M/W using, for example, benzaldehyde to afford resin 10®=M/W. Subsequent urea
formation gave 11®=M/W. The targeted hydantoin 12 was released from Merrifield resin (92%
overall yield) even at rt without base (Scheme 3). In contrast, Wang resin shows no release of
hydantoin after 4 days at rt. Release of 12 from Wang resin requires either prolonged heating
(refluxing THF, 3 days) or addition of base (Et3N). We attribute the facile cyclo-elimination of
12 from 11®=M (compared with 7®=M“8 which requires Et3N/THF/reflux) to a strong
buttressing effect in 11.8 Comparing release results from 11®=M and 11®=W suggests that the
Wang p-benzyloxy substituent produces an electron-donating effect on the ester carbonyl carbon
of the linker, which results in significant deactivation of the system to cyclo-elimination. By way
®
of contrast, it is noteworthy that the thiourea analogues of 7®=M/W and 11®=M/W undergo
cyclo-elimination to deliver the thiohydantoin analogues of 8 and 12 without requiring addition
of base.9
O
O
®
®
i. PhCHO, TMOF
DCM
H
N
NH2
O
O
ii. NaBH CN, AcOH
PhNCO
THF
3
THF, MeOH
9
10
Ph
O
HN
O
= M
®
O
N
®
r.t. without Et3N
N
NCH2Ph
O
O
= W
®
60 ˚C with Et N
3
12
11
Scheme 3.
Protocol for 11®=M“12: resin 9®=M (from 1 g of Merrifield resin, 0.68 mmol/g) was treated
with benzaldehyde (0.43 g, 4.08 mmol) in TMOF/THF (5 mL/5 mL) for 4 h at ambient
temperature, then washed with TMOF/THF (1:1). Subsequent addition of NaCNBH3 (85 mg,
1.36 mmol) in THF/MeOH/AcOH (9 mL/1 mL/0.1 mL) and agitating overnight at ambient
temperature, followed by washes with MeOH/THF (1:3), MeOH/DMF (1:3), DMF, and

7412
CH2Cl2, and gave Merrifield-derived resin 10®=M, which was dried under nitrogen. Merrifield-
derived resin 10®=M was treated with phenyl isocyanate (0.32 g, 2.72 mmol) in THF (10 mL) at
60°C overnight to sequentially effect urea formation (giving 11®=M) and cyclo-elimination to
produce hydantoin 12. The resin was washed with THF and the combined organic solvent was
evaporated under reduced pressure. The resulting residue was purified by short-pass column
chromatography (20% ethyl acetate in hexane) to give 12 (0.191 g, 0.63 mmol, 92%).10
Protocol for 11®=W“12: acid 5 (3 g, 8.89 mmol) and Wang resin (1.73 g, 2.22 mmol, 1.28
mmol/g) were coupled using DIC (1.12 g, 8.89 mmol) and DMAP (0.11 g, 0.89 mmol) following
the same procedure as above. The resultant resin 6 (PG=Fmoc) was treated with 20%
piperidine at ambient temperature for 1 h, washed with DMF and DCM, and dried to give
Wang-derived resin 9®=W. Reductive amination following the same procedure as for making
Merrifield-derived resin 10®=M afforded Wang-derived resin 10®=W. This resin was treated with
phenyl isocyanate (1 g, 8.89 mmol) in THF (10 mL) at rt for 10 h, washed with DMF, THF,
and DCM, and dried to afford the urea bound Wang-derived resin 11®=W. Treatment of this
resin with Et3N (0.9 g, 8.89 mmol) in THF (20 mL) at 60°C overnight, washes of the resin with
THF, and concentration of the combined filtrate afforded hydantoin 12 (0.638 g, 2.28 mmol,
94%) as a liquid.
These reactivity differences dictate the selection of Wang resin for library production targeting
N1-substituted hydantoins since Merrifield-derived resin suffers premature cyclo-elimination of
the final hydantoin product during filtration and resin washing. Merrifield resin can be
effectively employed in the production of N1-unsubstituted hydantoins.
Acknowledgements
We are grateful to the National Science Foundation for financial support of this research. The
400 MHz and 300 MHz NMR spectrometers used in this study were funded in part by a grant
from NSF (CHE-9808183).
References
1. Fields, G. B.; Tian, Z.; Barany, G. Principles and practice of solid-phase peptide synthesis. In Synthetic Peptides:
A User’s Guide; Grant, G. A., Ed. W. H. Freeman: New York, 1992; pp. 77–183.
2. (a) Park, K.-H.; Kurth, M. J. Drugs Fut. 2000, in press. (b) See Refs. 3, 4, and 5.
3. DeWitt, S. H.; Kieley, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad.
Sci. USA 1993, 90, 6909.
4. (a) See reference 3. (b) Kim, S. W.; Ahn, S. Y.; Koh, J. S.; Lee, J. H.; Ro, S.; Cho, H. Y. Tetrahedron Lett. 1997,
38, 4603. (c) Mattews, J.; Rivero, R. A. J. Org. Chem. 1997, 62, 6090. (d) Scicinski, J. J.; Barker, M. D.; Murray,
P. J.; Jarvie, E. M. Bioorg. Med. Chem. Lett. 1998, 8, 3609.
5. (a) Hanessian, S.; Yang, R. Y. Tetrahedron Lett. 1996, 37, 5835. (b) Dressman, B. A.; Spangle, L. A.; Kaldor,
S. W. Tetrahedron Lett. 1996, 37, 937. (c) Park, K.-H.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1998, 63,
6579. (d) Park, K.-H.; Abbate, E.; Najdi, S.; Olmstead, M. M.; Kurth, M. J. Chem. Commun. 1998, 1679.
6. See reference 5d.
1
7. 8: FTIR (KBr) 1778, 1702 cm−1; H NMR (300 MHz, CDCl3) l 7.44–7.35 (m, 5H), 6.96 (s, 1H), 5.81–5.72 (m,
1H), 5.25–5.19 (m, 2H), 4.18 (t, 2H, J=5.5 Hz), 2.71–2.65 (m, 2H), 2.56–2.48 (m, 2H). 13C NMR (75 MHz,
CDCl3) l 172.3, 156.8, 131.3, 130.8, 129.0, 128.2, 126.1, 120.3, 56.4, 35.9.
8. Park, K.-H.; Kurth, M. J. Tetrahedron Lett. 1999, 40, 5841.

7413
9. Thiodantoin analogues of 8 and 12 were prepared following the procedure described above except using phenyl
isothiocyanate. The thiourea analogues bound resin of 7 an 11 were not isolated. Thiohydantoin analogue 8 (94%
1
from Merrifield resin, 92% from Wang resin): FTIR (thin film) 1750 cm−1; H NMR (300 MHz, CDCl3) l 8.07
(s, 1H), 7.54–7.51 (m, 3H), 7.48–7.28 (m, 2H), 5.82–5.79 (m, 1H), 5.32–5.26 (m, 2H), 4.33 (dd, 1H, J=7.57, 4.24
Hz), 2.82–2.75 (m, 1H), 2.61–2.54 (m, 1H); 13C NMR (75 MHz, CDCl3) l 183.8, 172.8, 132.5, 130.5, 129.3, 129.2,
128.2, 120.9, 59.2, 35.6. Thiohydantoin analogue 12 (90% from Merrifield resin, 93% from Wang resin): FTIR
1
(thin film) 1750 cm−1; H NMR (300 MHz, CDCl3) l 7.51–7.23 (m, 10H), 5.87 (d, 1H, J=15.0 Hz), 5.70–5.60
(m, 1H), 5.27–5.22 (m, 2H), 4.42 (d, 1H, J=15.0 Hz), 4.11 (t, 1H, J=4.2 Hz), 2.74 (m, 2H); 13C NMR (75 MHz,
CDCl3) l 183.0, 172.2, 134.7, 133.4, 129.3, 129.1, 129.0, 128.4, 128.3, 121.1, 60.7, 48.5, 33.1.
1
10. 12: FTIR (thin film) 1773, 1710 cm−1; H NMR (300 MHz, CDCl3) l 7.50–7.11 (m, 10H), 5.66–5.61 (m, 1H),
5.24–5.18 (m, 2H), 5.13 (d, 1H, J=15.3 Hz), 4.17 (d, 1H, J=15.3 Hz), 4.00 (t, 1H, J=4.2 Hz), 2.70–2.65 (m, 2H);
13C NMR (75 MHz, CDCl3) l 177.2, 155.5, 135.4, 131.7, 130.0, 129.0, 128.9, 128.3, 128.2, 128.1, 126.0, 120.7,
58.1, 44.9, 32.9.
.