866
D.-X. Wang et al. / Tetrahedron Letters 43 (2002) 865–867
linkage such as Pac (Phenacyl ester), which are very
labile to nucleophilic attack, leading to cyclization via
intramolecular aminolysis.
the removal of the Boc group by mixing resin 2 with
3.5N HCl/HOAc for 30 min and washing with EtOAc
(×5), a solution of 3 equiv. Boc-AA-OH, 3 equiv.
HOBt, 3.2 equiv. DCC and 1.2 equiv. N-methylmor-
pholine in DMF was mixed with the resin for 4–6 h.
Resin 3 was filtrated and washed with DMF (×3),
MeOH (×5) and DCM (×2). The completeness of the
second residue assemblage was monitored by ninhydrin
test.13 For the Boc deprotection, resin 3 was treated as
before. Neutralization and washing were accomplished
with 10% DIPEA/EtOAc (2 min), 95% EtOH (3×1
min). After draining, the resin 4 was mixed with 5%
Et3N in THF–H2O (8:1) for 24 h. The supernatant was
collected and concentrated. DKP product 5 was precip-
itated by mixing the residual solution with ether. Eigh-
teen DKPs were synthesized in good yields (Table 1).
An effort was initiated in the present study to establish
a simple procedure for the efficient synthesis of DKPs
on bromoacetyl resin, as shown in Scheme 1. Function-
alized resin 1 was prepared from PS (polystyrene, 1%
DVB cross-linked, 100–200 mesh) beads by Friedel–
Crafts acylation.12 The yield was estimated by the
weight gain of the resin. The anchorage of the first
N-Boc-amino acid on the resin was carried out under
mild conditions—mixing 1 with Boc-AA-OH and Et3N,
in DMF, at room temperature for 24 h. Ester 2 was
produced in near quantitative yield based on the weight
gain of the resin. The second residue was added to the
resin by use of a standard DCC/HOBt coupling proce-
dure after removal of the Boc group from 2. The target
compound 5 was obtained directly by eliminating the
Boc group from 3 and then mixing with Et3N and
THF. However, the final product was inevitably con-
taminated with the by-product HCl·Et3N, and was very
difficult to purify. It was obvious that preneutralization
and washing before DKP-ring closure in a stepwise
manner (route B as shown in Scheme 1) instead of
route A was necessary to ensure the purity of 5. Great
care was taken to minimize premature DKP-ring clos-
ing during neutralization and washing. The use of the
hindered base DIPEA (diisopropylethylamine) instead
of Et3N and shortening the washing time were impera-
tive in our protocol.
In summary, a facile and efficient method for the
solid-phase synthesis of DKPs from a resin bound
OPac linker has been developed. The reaction can be
conveniently carried out under mild conditions, and
preneutralization treatment ensured a DKP product
with excellent purity. Although most of the DKP
derivatives prepared in the present study consisted of at
least one of the following hindered residues such as
Phe, Val, Trp, Arg, Tyr(ClzB), His(Bzl), the yields were
reasonable or even better. It is obvious that the lability
of the OPac linkage to nucleophilic attack is suitable
for the synthesis of DKPs by solid-phase methods and
maybe by solution phase also. This will be amenable to
the preparation of diverse DKP libraries for the study
of combinatorial chemistry in the near future.
A typical experimental procedure is as follows: A sus-
pension of 1 (1 mmol) in DMF containing Et3N (2.2
mmol) and Boc-AA-OH (2 mmol) was stirred at room
temperature for 24 h. The liquid was drained off and
the resin was washed successively with DMF (×3), 95%
EtOH (×5), EtOAc (×2) and DCM (×1). Yields of 2
were evaluated from the weight gain of the resin. After
Acknowledgements
The authors would like to thank Dr. Jeper Abliz and
his assistants for providing mass spectral data.
Table 1. Results of the preparation of DKPs
Entry
Compounds
Mp (°C)
Yields (%)
Mw (calcd)
FAB-MS
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
cyclo[Met-Phe]
cyclo[Trp-Phe]
cyclo[Lys-Phe]
cyclo[Met(Mob)-Phe]
cyclo[Pro-Phe]
cyclo[Gln-Phe]
cyclo[Arg-Phe]
cyclo[Pro-Val]
cyclo[Pro-Gln]
cyclo[Pro-His(Bzl)]
cyclo[Pro-Arg]
cyclo[Glu(Obzl)-Trp]
cyclo[Glu-Tyr(ClzB)]
cyclo[Pro-Tyr(ClzB)]
cyclo[Arg-Asn]
cyclo[Gln-Asn]
cyclo[Met-Asn]
cyclo[Ala-Lys]
140–142
\280
79
60
71
66
82
76
72
81
85
79
84
72
71
73
80
71
77
67
278.4
333.4
275.4
370.5
244.3
275.3
303.4
196.3
225.2
324.4
253.3
405.4
451.3
419.3
270.3
242.2
245.3
199.3
279.1
334.1
276.2
371.2
245.2
276.2
304.1
197.1
226.2
325.2
254.2
406.2
451/453
419/421
271.2
243.1
246.2
200.1
253–255
178–180
118–120
232–234
133–135
175–178
161–163
193–195
183–185
170–172
217–219
215–217
200–202
168–170
113–115
179–181
Wang, De-Xin
