Synthesis of 2-substituted endo-hymenialdisine derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.01.114

The first synthesis of 2-substituted endo-hymenialdisine derivatives 1-4 is described started with 2-substituted pyrroles and 5-substituted pyrrolo-2-carboxylic acids.

Full text of DOI:10.1016/j.tetlet.2007.01.114

Tetrahedron Letters 48 (2007) 1899–1901
Synthesis of 2-substituted endo-hymenialdisine derivatives
Qinfei He, Wei Chen and Yong Qin*
Department of Chemistry of Medicinal Natural Products and Key Laboratory of Drug Targeting, West China School of
Pharmacy, and State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, PR China
Received 20 October 2006; revised 21 January 2007; accepted 23 January 2007
Available online 25 January 2007
Abstract—The first synthesis of 2-substituted endo-hymenialdisine derivatives 1–4 is described started with 2-substituted pyrroles
and 5-substituted pyrrolo-2-carboxylic acids.
Ó 2007 Published by Elsevier Ltd.
The marine natural product hymenialdisine was origi-
H2N
HN
H2N
HN
N
N
nally isolated from the sponges Axinella verrucosa and
Acantella aurantiaca.1 Hymenialdisine has revealed low
nanomolar inhibition activities against a panel of
kinases such as GSK-3b, members of the CDK family,
Erk1, Erk2, CK1, and MEK.2,3 The chemical structure
and kinase inhibition activity of four known hymeni-
aldisine analogues are presented in Figure 1. Comparing
the inhibition activities among these analogues, the inhi-
bition activity of hymenialdisine is about 80-fold higher
than that of the debromo one against kinase MEK-1.
The inhibition activity of diacetyl hymenialdisine is
about 4-fold higher against kinase GSK-3b and is about
2-fold higher against kinase CDK5 than that of de-
bromo diacetyl hymenialdisine. In the X-ray structure
of hymenialdisine–CDK2 complex,2 some level of
hydrophobic interaction between the bromine atom
and the hydrophobic backbone of CDK2 is observed.
Therefore, the bulky and lipophilic effects of the bromo
atom of hymenialdisine could play a key role in gaining
the high inhibition potency.
O
O
NH
NH
Br
N
N
H
H
O
O
Hymenialdisine
GSK-3 , IC50 10 nM
CDK5, IC50 28 nM
MEK-1, IC50 9 nM
Debromohymenialdisine
MEK-1, IC50 824 nM
β
Ac2N
HN
Ac2N
HN
N
N
O
O
NH
NH
Br
N
N
H
H
O
O
Diacetyldebromo-
hymenialdisine
Diacetylhymenialdisine
GSK-3 , IC50 160 nM
CDK5, IC50 1500 nM
β
GSK-3
β
, IC50 600 nM
CDK5, IC50 3000 nM
The chemical structure modification of natural product
possessing superior bioactivity is considered as the most
efficient way to find drug candidates, which have high
potency and selectivity. Lack of inhibition selectivity is
the main characteristics and disadvantage of hymeni-
aldisine. In view of the inhibition potency gained by
the bromo substituent, the chemical modification of
hymenialdisine is anticipated to be focused on replacing
Figure 1. Chemical structure and kinase inhibition activity of hymeni-
aldisine analogues.
the bromo atom with other lipophilic substituents at the
a-position of the pyrrolyl ring. In this Letter, we report the
first synthesis of four endo-hymenialdisine derivatives
1–4 by substituting the bromo atom with methyl, benzyl,
phenyl, and tert-butyl groups, respectively (Fig. 2).
The synthesis of hymenialdisine derivatives 1–4 was
commenced with 2-substituted pyrroles4 and 5-substi-
tuted pyrrolo-2-carboxylic acids.5 As shown in Scheme
1, three methods were used to link 2-substituted pyrrolyl
Keywords: Synthesis; Hymenialdisine; a-Substituted pyrrole; Kinase
inhibitor.
*
Corresponding author. Tel./fax: +86 28 85503842; e-mail addresses:
yongqin@scu.edu.cn; yanshuqin@yahoo.com
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.114

1900
Q. He et al. / Tetrahedron Letters 48 (2007) 1899–1901
H2N
HN
H3COOC
HOOC
N
O
PPA / P2O5
120 oC
1N NaOH
N
NH
1, R = Me; 2, R = Bn
3, R = Ph; 4, R = tBut
R
R
N
N
H
R1
H
O
O
NH
17, R = Me
18, R = Bn
19, R = Ph
20, R = tBut
8, R = Me, R1 = H
9, R = Bn, R1 = H
R
N
H
O
11, R = Ph, R1 = H
16, R = tBut, R1 = CO2Me
Figure 2. 2-Substituted endo-hymenialdisine derivatives.
14
H2N
N
13
O
MeS
N
HN
12
3
O
11
5
O
25
1) NH3 in dioxane
2) NH3 in MeOH
O
6
Cl-
PhCON
MeOOC
7
H3+N
OMe
2
7
TiCl4 / pyridine
CH2Cl2, -10 oC
NH
ClCOCCl3
NH
NH
R
R
R
N
8
N
1
R
N
H
R
9
O
COCCl3
N
N
H
H
O
K2CO3,Et2O
Et3N, MeCN
O
H
H
21, R = Me, 35%
22, R = Bn, 76%
23, R = Ph, 55%
24, R = tBut, 45%
1, R = Me, 50%
2, R = Bn, 32%
3, R = Ph, 24%
4, R = tBut, 30%
8, R = Me, 61%
9, R = Bn, 45%
5, R = Me
6, R = Bn
R=Bn, Me
H2N
HN
N
O
H3COOC
NH
NH
26, R = Me; 27, R = Bn
28, R = Ph; 29, R = tBut
R
SOCl2
N
7, Et3N
H
COOH
O
Ph
Ph
N
N
COCl
toluene
Ph
N
CH2Cl2
67%
H
O
H
H
Scheme 2. Syntheses of 2-substituted endo-hymenialdisine derivatives
1–4.
11
10
H3COOC
H3COOC
5-Subtituted pyrrolo-2-carboxamides 8, 9, 11, and 16
were first converted to the corresponding acids 17–20
by hydrolysis with 1 N HCl. After intra-molecular cycli-
zation by using PPA and P2O5 under nitrogen at
120 °C,6 the key intermediates 21–24 were obtained with
yields of 35%, 76%, 55%, and 45%, respectively. The
guanidine moiety was then successfully installed on the
azepine ring by utilizing the recent reported one-pot
three-step methodology.6b Thus, condensations of 21–
24 with 1-benzoyl-2-methylsulfanyl-1,5-dihydroimi-
daol-4-one 24 in the presence of TiCl4 and pyridine, fol-
lowed by two-step ammonia hydrolysis (first with
diluted ammonia solution in dioxane for 0.5 h, subse-
quently with saturated ammonia solution in MeOH
for 4 h) provided 2-substituted endo-hymenialdisine
derivatives 1–4 in low to moderate yields without isola-
tion of exo-isomers 26–29. Attempts of isomerization of
endo-hymenialdisine derivatives 1–4 into the corre-
sponding exo-isomers 26–29 were unsuccessful by irradi-
ation of compounds 1–4 with microwave in aqueous
ammonia according to the literature method for the
isomerization of endo-debromohymenialdisine.6b Fail-
ure to shift 5,6-double bond to 5,11-double is due to
the existence of 2-substituents at the pyrrolyl ring, which
precludes the aromatic isomerization of the conjugated
system under the same reaction condition. In other
words, the aromatic isomerization of endo-hymenialdi-
sines 1–4 probably requires higher energy compared to
that of endo-debromohymenialdisine.
N
R1
NH
1) SOCl2, toluene
N
2) Et3N, 7, MeCN
N
H
O
H
O
13
16 R1=COOMe
COOH
N
H
12
ClCOOMe, Et3N
7, THF, 80%
MeOOC
O
O
NH
MeO
OMe
N
H
O
+
O
14
15
Scheme 1. Synthesis of 5-subtituted pyrrolo-2-carboxamides.
moiety with b-alanine. When 2-methylpyrrole or 2-benz-
ylpyrrole reacted with trichloroacetyl chloride in the
presence of K2CO3 in Et2O, 5-substituted 2-trichloro-
acetylpyrroles 5 and 6 were obtained in almost quantita-
tive yields. Without purification, the crude compounds 5
and 6 were used directly to condense with b-alanine
methyl ester hydrochloride 7 in MeCN by using Et3N
as a base to produce compounds 8 and 9 with yields
of 61% and 45%, respectively. Compound 11 was ob-
tained in 67% yield by transferring 5-phenylpyrrolo-2-
carboxylic acid into its acyl chloride 10 first, followed
by condensation with 7. However, 5-tert-butylpyrrolo-
2-carboxylic acid 12 failed to produce compound 13 in
the same synthetic approach for the preparation of 11.
As an alternate approach, compound 16 with a meth-
oxycarbonyl protecting group on the amide nitrogen
was prepared with 80% yield by treatment of 12 with
7, methyl chloroformate, and Et3N in THF at room
temperature for 8 h. The conversion of 12 into amide
16 was most likely to proceed through the reaction of
anhydride 14 with in situ formed N-methoxycarbonyl
b-alanine methyl ester 15.
The geometric position of 5,6-double bond was unam-
1
biguously confirmed by the H NMR spectra.7 In the
1H NMR (400 MHz, DMSO-d6 + D2O) of the synthe-
sized endo-isomers 1–14, the singlet attributed to C11
methyne proton appeared at 4.60 ppm for 1, 4.65 ppm
for 2, 4.71 ppm for 3, and 4.66 ppm for 4. The triplet
attributed to C6 olefinic proton appeared at 5.77 ppm
for 1, 5.80 ppm for 2, 5.87 ppm for 3, and 5.83 ppm
for 4.
At this stage, preparation of the 2-substituted pyr-
rolo[2,3-c]azepin-4,8-dione intermediates 21–24 from
acids 17–20 became the main concern (Scheme 2).

Q. He et al. / Tetrahedron Letters 48 (2007) 1899–1901
1901
L. C. Can. J. Chem. 1964, 42, 1279; (c) Anserson, H. J.;
Huang, C. W. Can. J. Chem. 1970, 48, 1550.
6. (a) Annoura, H.; Tatsuoka, T. Tetrahedron Lett. 1995, 36,
413; (b) Papeo, G.; Posteri, H.; Borghi, D.; Varasi, M. Org.
Lett. 2005, 7, 5641.
In summary, an efficient synthesis of 2-substituted endo-
hymenialdisine derivatives 1–4 has been achieved, which
is the first report of endo-hymenialdisine derivatives with
a variety of substituents at the a-position of the pyrrolyl
ring. The synthesized compounds have stable chemical
structures, all of which will be subjected to bioactivity
screening as promising kinase inhibitors.
7. Analytic data of 2-substituted endo-hymenialdisine deriva-
tives 1–4 are listed as below:
Compound 1, isolated by chromatography (CH2Cl2/MeOH
saturated with NH3 4:1) as a light-yellow solid, mp: 261–
1
262 °C. IR: 3374, 3253, 1703, 1615, 1497 cmÀ1; H NMR
(400 MHz, DMSO-d6 + D2O) d 5.83 (s, 1H), 5.77 (t,
J = 6.0 Hz, 1H), 4.60 (s, 1H), 3.28–3.42 (m, 2H), 2.15 (s,
3H) ppm; 13C NMR (200 MHz, DMSO-d6) d 188.3, 172.1,
164.4, 135.9, 133.1, 124.7, 124.5, 123.6, 105.7, 65.6,
13.2 ppm. HRMS calcd for C12H13N5O2 (M+Na+):
282.0969. Found: 282.0959.
Acknowledgments
This work was supported by NSFC (No. 20372048),
Ministry of Education (NCET, RFDP, and EYTP),
and Sichuan Province Government (Nos. 04ZQ026-
011 and 05SG022-030).
Compound 2, isolated by chromatography (CH2Cl2/MeOH
saturated with NH3 8:1) as a light-yellow solid, mp: 226–
;
228 °C. IR: 3239, 1692, 1630, 1492 cmÀ1 1H NMR
References and notes
(400 MHz, DMSO-d6 + D2O) d 7.18–7.56 (m, 5H), 5.88
(s, 1H), 5.80 (t, J = 6.8 Hz, 1H), 4.65 (s, 1H), 3.84 (s, 2H),
3.28–3.44 (m, 2H) ppm; 13C NMR (200 MHz, DMSO-d6) d
187.2, 172.1, 163.7, 139.9, 136.1, 135.3, 128.7, 128.6, 128.5,
128.4, 126.2, 124.9, 123.7, 122.1, 105.2, 64.9, 37.9,
33.1 ppm. HRMS calcd for C18H18N5O2 (M+H+):
336.1461. Found: 336.1467.
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Compound 3, isolated by chromatography (CH2Cl2/MeOH
saturated with NH3 6:1) as a light-yellow solid, mp: 253–
;
255 °C. IR: 3346, 1393, 1632, 1481 cmÀ1 1H NMR
(400 MHz, DMSO-d6 + D2O) d 7.71 (d, J = 8.0 Hz, 2H),
7.38 (t, J = 8.0 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 6.57 (s,
1H), 5.87 (t, J = 6.8 Hz, 1H), 4.71 (s, 1H), 3.36–3.49 (m,
2H) ppm; 13C NMR (200 MHz, DMSO-d6) d 186.8, 171.7,
163.4, 135.6, 134.7, 131.6, 128.9, 128.7, 127.3, 127.2, 125.4,
125.1, 124.3, 123.1, 104.5, 64.6, 37.6 ppm. HRMS calcd for
C17H16N5O2 (M+H+): 322.1305. Found: 322.1293.
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Compound 4, isolated by chromatography (CH2Cl2/MeOH
saturated with NH3 10:1) as a light-yellow solid, mp: 265–
1
267 °C. IR: H NMR (400 MHz, DMSO-d6 + D2O) d 5.95
(s, 1H), 5.83 (t, J = 6.8 Hz, 1H), 4.66 (s, 1H), 3.34–3.49 (m,
2H), 1.26 (s, 9H) ppm; 13C NMR (200 MHz, DMSO-d6) d
187.3, 172.2, 163.6, 145.6, 144.2, 136.1, 125.3, 122.7, 101.6,
65.1, 37.9, 34.9, 30.1 ppm. HRMS calcd for C15H20N5O2
(M+H+): 302.1618. Found: 302.1605.