Preparatory study for the synthesis of the marine sponge alkaloids asmarines A-F: Synthesis of their heterocyclic portions

Article abstract of DOI:10.3987/COM-02-9512

A synthesis of three tricyclic compounds (1c), (2c), and (3c), selected as models for the heterocyclic portions of the marine sponge alkaloids asmarines A-F, has been accomplished through cyclization of the 7-alkyl-6-chloropurine derivatives.

Full text of DOI:10.3987/COM-02-9512

HETEROCYCLES, Vol. 57, No. 7, 2002, pp.1235 - 1238, Received, 13th May, 2002
PREPARATORY STUDY FOR THE SYNTHESIS OF THE MARINE SPONGE
ALKALOIDS ASMARINES A–F: SYNTHESIS OF THEIR HETEROCYCLIC
PORTIONS
a,
b
Masashi Ohba * and Takahiro Tashiro
a
Center for Instrumental Analysis, Kanazawa University, Takara-machi, Kanazawa
9
20-0934, Japan
b
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kana-
zawa 920-0934, Japan
Abstract - A synthesis of three tricyclic compounds (1c), (2c), and (3c), selected
as models for the heterocyclic portions of the marine sponge alkaloids asmarines
A–F, has been accomplished through cyclization of the 7-alkyl-6-chloropurine de-
rivatives.
1
Asmarines A (1a) and B (1b), novel purine-related alkaloids isolated from the Red Sea sponge Raspailia
2
sp., display significant cytotoxicity against four human cancer cell lines. The same sponge is further
known to contain four closely related alkaloids, i.e., asmarines C (2b), D (2a), E (3a), and F (3b), al-
2
b
though none of them have been isolated in pure forms. The structures of these alkaloids were elucidated
through extensive spectral studies in conjunction with an X-Ray crystallographic analysis of asmarine A
2
a
3
(
1a). In connection with our ongoing interest in the synthetic study of purine alkaloids, we sought pos-
sible synthetic routes to the heterocyclic models (1c), (2c), and (3c) possessing a [1,4]diazepino[1,2,3-
gh]purine skeleton as a preliminary to the total synthesis of asmarines A–F.
R1
R1
R1
R2
R2
R2
1
2
HO10N
11
HN
MeO
N
13
6
N 7
N
N
1N
N
N
8
O
O
2
N
N
N
N
3
N
N
9
Me
Me
1
2
3
CH2–
CH2–
H
H
1
2
1
2
1
2
a: R = Me; R =
b: R = Me; R =
c: R = R = H

The synthesis of the tricyclic hydroxylamine (1c), selected as a model for a common heterocyclic portion of
asmarines A and B, was first investigated. Kashman and co-workers have recently reported the construc-
6
tion of a [1,4]diazepino[1,2,3-gh]purine system via intramolecular alkylation at the N -position of 9-
6
benzyl-N -benzyloxy-7-(3-chloropropyl)adeninium salt without description of the removal of two benzyl
4
groups. Toward the development of a route applicable to the synthesis of asmarines, we envisioned that
intramolecular amination at the 6-position of an appropriate 7-(3-hydroxyaminopropyl)-6-chloropurine (5)
6
(
route b) would be preferable to cyclization at the N -position of the adenine derivative (4) (route a), be-
cause the latter route is presumed to be more difficult in constructing the stereogenic center at the 11-
position of asmarines. At the outset of the present synthesis, therefore, we needed the 7-alkylated 6-
5
chloropurine (5).
HO
RONH (CH ) X
N
Cl (CH ) NHOR
2
3
2 3
6
6
N
N
N
N 7
N
a
N
b
N
N
N
N
N
N
9
4
1c
5
6
7
Since direct alkylation of 6-chloropurine using alkyl halide and a base or under Mitsunobu conditions has
been reported to occur at the 9-position predominantly over the 7-position, we investigated an alternative
route via cyclization of pyrimidine derivative to obtain the requisite purine (5). On treatment of the forma-
mide (6) in DMF with the bromide (7) (K CO , Bu NI, room temperature, 24 h) according to a prece-
2
3
4
8
dent, the N-alkylated formamide (8) was obtained in 74% yield. Subsequent base-promoted cyclization of
was very slow in DMF, but proceeded smoothly in 1-BuOH (35–40 °C, 2 h) to afford the desired 7-
8
alkylated 6-chloropurine (9) in 87% yield. Removal of the Alloc group of 9 with Pd catalyst in the pres-
9
ence of 2-ethylhexanoic acid (CH Cl –Et O, room temperature, 1.5 h) and intramolecular amination at the
2
2
2
6
-position of the resulting amine using Et N (1-BuOH, reflux, 2 h) provided the tricyclic compound (10)
3
containing a [1,4]diazepino[1,2,3-gh]purine skeleton in 75% yield. Finally, deprotection of 10 with concd
1
0
HCl (THF, 55 °C, 1.5 h) gave the first target (1c) (mp 204–205 °C) in 86% yield.
Alloc
Alloc
(
CH ) NOMOM
Cl
Alloc
Cl
N
2 3
Cl (CH ) NOMOM
2
3
NHCHO
NH2
NCHO
Br(CH ) NOMOM (7)
K CO
3
N
2
3
2
N
N
N
K CO , Bu NI, DMF
1-BuOH
N
2
3
4
N
NH2
N
6
8
9
1
. Pd(PPh ) , PPh
3 4 3
MOMO
HO
Ac
N
N
10N
2-ethylhexanoic acid
CH Cl –Et O
N
N
concd HCl
THF
N
N
Ac2O
N
N
2
2
2
N
N
N
2
. Et N, 1-BuOH
MeOH
3
N
N
MeO
N
1
0
1c
11

In connection with the structure elucidation of asmarine B (1b), Kashman and
co-workers further described the reaction of 1b with excess acetic anhydride in
MeOH to produce 12 via a four-step mechanism: acetylation of the NOH
group,a [3,3] sigmatropic rearrangement, 1,6-addition of MeOH, and elimina-
H
1
1
HN
2
b
tion of acetic acid.
On treatment with excess acetic anhydride in MeOH at
N
N
N
room temperature for 30 h, the hydroxylamine (1c) also afforded 11 in 71%
yield. Concomitant acetylation at the 10-position in the latter is probably due to
no sterically congested environment compared to 12, which possesses two sub-
stituents at the 11-position.
MeO
N
1
2
Cl (CH ) NHBoc
HN
2
3
N
1. CF CO H, CH Cl
2
N
N
Br(CH ) NHBoc (14)
N
3
2
2
N
2
3
O
O
O
K CO , Bu NI, DMF
N
2. Et3N, 1-BuOH
2
3
4
N
N
Cl
N
H
N
Me
Me
15
2c
N
O
OMe
N
MeO
Cl (CH ) NBoc
N
2
3
Me
OMe
1
3
N
1. CF CO H, CH Cl
3 2 2 2
N
N
N
Br(CH ) NBoc (16)
2
3
O
2
. Et N, 1-BuOH
K CO , Bu NI, DMF
N
3
N
2
3
4
N
N
Me
Me
1
7
3c
Our attention was next turned to the synthesis of two heterocyclic models (2c) and (3c) for asmarines C
(2b), D (2a) and asmarines E (3a), F (3b), respectively. Based on the results obtained with 1c, we se-
1
1,12
lected the 8-oxopurine (13)
as a starting material. Alkylation of 13 with the bromide (14) in DMF
(
K CO , Bu NI, room temperature, 22 h) proceeded at the 7-position, giving 15 in 99% yield. Removal
2 3 4
of the Boc group and subsequent cyclization with Et N (1-BuOH, reflux, 2 h) produced the second target
3
(
(
2c) (mp 286.5–287.5 °C) in 98% yield. A parallel sequence of reactions starting from 13 and the bromide
1
13
16) provided the third target (3c) (mp 146–147 °C) through 17 in 76% overall yield. The H- and C-
NMR spectral signals of the model compounds (1c), (2c), and (3c) thus synthesized were similar, except
for those affected by two substituents at the 11-position, to the corresponding signals of 1a,b, 2a,b, and
3
a,b, respectively.
In conclusion, we have achieved the synthesis of three tricyclic models (1c), (2c), and (3c) for the hetero-
cyclic portions of the marine sponge alkaloids asmarines A–F. The correctness of the structures proposed
for the heterocyclic moieties in these alkaloids has been supported as a result of the present synthesis.
ACKNOWLEDGEMENT
This work was supported by a Grant-in-Aid for Scientific Research (C) (No. 12672051) from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.

REFERENCES AND NOTES
1
. For a review on the purine alkaloids, see: Atta-ur-Rahman and M. I. Choudhary, ‘The Alkaloids,’ Vol.
8, ed. by A. Brossi, Academic Press, New York, 1990, pp. 225–323.
3
2
. (a) T. Yosief, A. Rudi, Z. Stein, I. Goldberg, G. M. D. Gravalos, M. Schleyer, and Y. Kashman,
Tetrahedron Lett., 1998, 39, 3323; (b) T. Yosief, A. Rudi, and Y. Kashman, J. Nat. Prod., 2000, 63,
2
99.
3
. (a) M. Ohba, N. Kawase, T. Fujii, K. Aoe, K. Okamura, R. Fathi-Afshar, and T. M. Allen, Tetrahe-
dron Lett., 1995, 36, 6101; (b) M. Ohba, N. Kawase, and T. Fujii, Heterocycles, 1995, 41, 2661;
(
c) M. Ohba, N. Kawase, and T. Fujii, J. Am. Chem. Soc., 1996, 118, 8250; (d) M. Ohba, K. Ii-
zuka, H. Ishibashi, and T. Fujii, Tetrahedron, 1997, 5 3, 16977.
4
5
. D. Pappo, A. Rudi, and Y. Kashman, Tetrahedron Lett., 2001, 4 2, 5941.
. It is known that amination of 6-chloro-9-(2-tetrahydropyranyl)purine with α,α-dimethylallylamine, a
sterically congested amine possessing an adjacent quarternary carbon like asmarines, provides 6-(α,α-
1
3
dimethylallylamino-9-(2-tetrahydropyranyl)purine.
6
. (a) J. A. Montgomery and C. Temple, Jr., J. Am. Chem. Soc., 1961, 83, 630; (b) G. B. Elion, J.
Org. Chem., 1962, 27, 2478; (c) H. J. Schaeffer and R. Vince, J. Med. Chem., 1965, 8, 33; (d) T. C.
McKenzie and J. W. Epstein, J. Org. Chem., 1982, 47, 4881; (e) J. L. Kelley, M. P. Krochmal, J. A.
Linn, E. W. McLean, and F. E. Soroko, J. Med. Chem., 1988, 31, 606; (f) L.-L. Gundersen, A. K.
Bakkestuen, A. J. Aasen, H. Øverås, and F. Rise, Tetrahedron, 1994, 5 0, 9743.
7
. (a) W. A. Szarek, C. Depew, H. C. Jarrell, and J. K. N. Jones, J. Chem. Soc., Chem. Commun.,
1
975, 648; (b) M. Iwakawa, B. M. Pinto, and W. A. Szarek, Can. J. Chem., 1978, 56, 326; (c) A.
Toyota, N. Katagiri, and C. Kaneko, Chem. Pharm. Bull., 1992, 40, 1039; (d) S. Kozai and T. Ma-
ruyama, Chem. Pharm. Bull., 1999, 4 7, 574.
8
9
. J. A. Montgomery and K. Hewson, J. Org. Chem., 1961, 2 6, 4469.
. P. D. Jeffrey and S. W. McCombie, J. Org. Chem., 1982, 4 7, 587.
1
1
1
0. The elemental analysis pointed to the formula C H N O·1/2H O.
8 9 5 2
1. N. J. Kos, H. C. van der Plas, and W. J. F. Blees, J. Org. Chem., 1983, 4 8, 850.
2. 6-Chloro-7,9-dihydro-9-methyl-8H-purin-8-one (13) was prepared from 5-amino-4-chloro-6-(methyl-
1
1
amino)pyrimidine in 80% yield according to the literature procedure but with some modification (urea,
DMF, reflux, 4 h).
1
3. F. Skoog, H. Q. Hamzi, A. M. Szweykowska, N. J. Leonard, K. L. Carraway, T. Fujii, J. P. Hel-
geson, and R. N. Loeppky, Phytochemistry, 1967, 6, 1169.