Synthesis of (+)-agelasine D from (+)-manool

Article abstract of DOI:10.1016/j.tetlet.2004.04.030

(+)-Agelasine D, originally isolated from the marine sponge Agelas nakamurai, is synthesized for the first time. The terpenoid side chain was readily available from the diterpene alcohol (+)-manool.

Full text of DOI:10.1016/j.tetlet.2004.04.030

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4233–4235
Synthesis of (+)-agelasine D from (+)-manool
Bibigul T. Utenova and Lise-Lotte Gundersen*
Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
Received 27 February 2004; revised 30 March 2004; accepted 7 April 2004
Abstract—(+)-Agelasine D, originally isolated from the marine sponge Agelas nakamurai, is synthesized for the first time. The
terpenoid side chain was readily available from the diterpene alcohol (+)-manool.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Agelasines are 7,9-dialkylpurinium salts isolated from
marine sponges. At the present a total of 11 9-methyl-
adeninium salts, agelasine A-I, epiagelasine C, and agelin
B, has been isolated from Agelas species.1 All compounds
carry a diterpenoid side chain in the adenine 7-position.
Until now, only ())-agelasine A,2 ())-agelasine B,3 and
( )-agelasine F,4 have been synthesized. The agelasines
are associated with bioactivities such as antimicrobial
and cytotoxic effects as well as contractive responses of
smooth muscles and inhibition of Na, K-ATPase.1;5 We
herein report the first synthesis of (+)-agelasine D.1a;d
The starting material for the terpenoid side chain is the
readily available (+)-manool, and, at least formally, also
the less expensive ())-sclareol6 (Scheme 1).
nium salt. However, alkylation on 9-substituted adenine
gives mainly 1,9-dialkyl derivatives, and when 7-alkyl-
adenines are reacted with alkyl halides, the second N-
substituent is preferably introduced on N-3.7 Treatment
of N-alkoxy-9-methyl-9H-purin-6-amines8;9 with alkyl-
ating agents results, on the other hand, in the desired
alkylating pattern.7
The alkyl halide necessary for the introduction of the N-
7 terpenoid substituent in agelasine D was generated by
bromination of (+)-manool employing phosphorus
tribromide (Scheme 2).10 The best E/Z-selectivity
obtained was 85:15 and the crude bromide 1 was used
directly for alkylation of the purine derivative 2.
Attempts to generate the pure E allylic bromide 1 by
treatment of manoyl acetate with TMS–bromide and
zinc iodide11 gave less satisfactory results.
Synthesis of agelasines requires regioselective alkylation
of an adenine derivative to give a 7,9-dialkylated puri-
H
H
H
NH2
HO
HO
HO
N
N
Cl
ref. 6
N
N
Me
(+)-Manool
(+)-Agelasine D
(-)-Sclareol
Scheme 1.
Keywords: Allylation; Halogenation; Marine metabolites; Purines; Terpenes and terpenoids.
* Corresponding author. Tel.: +47-228-57019; fax: +47-228-55507; e-mail: l.l.gundersen@kjemi.uio.no
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.030

4234
B. T. Utenova, L.-L. Gundersen / Tetrahedron Letters 45 (2004) 4233–4235
H CO
1)
3
N
H
N
N
HN
H
DMA, 50 oC,
21 h
N
2
Me
PBr3, pyridine
Et2O, -35 oC, 1h
1
HO
2) CH2Cl2,MeOH,NH3(aq), SiO2
81%
E:Z=85:15
(+)-Manool
Br
H
H
Zn, AcOH,
MeO
MeOH-H2O (2:1)
NH2
N
N
N
50 oC, 15 h
N
N
N
60%, E:Z = 8:2
N
Pure E -3 (43%)
Cl
N
after cryst.
N
Me
Me
3
(+)-Agelasine D
+
51%
H
H3CO
N
N
27%
E:Z=8:2
N
N
N
4
Me
Scheme 2.
As in the previously reported syntheses of agelasines,2–4
alkylation of the methoxyadenine 2 gave a mixture of
the desired product 3 as well as the N6 alkylated isomer
412 (Scheme 2). After separation of the products by flash
chromatography employing an eluent mixture contain-
ing ammonia, the major product was isolated as an E/Z
mixture of the betaine 3. The pure E-3 was obtained
after crystallization from EtOAc. Finally the N-methoxy
group was removed reductively to give the target com-
pound, (+)-agelasine D.13
Nakamura, H.; Kobayashi, J.; Ohizumi, Y. Tetrahedron
Lett. 1984, 25, 3719–3722; (c) Capon, R. J.; Faulkner, D.
J. J. Am. Chem. Soc. 1984, 106, 1819–1822; (d) Wu, H.;
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Y.; Hirata, Y. Bull. Chem. Soc. Jpn. 1986, 59, 2495–2504;
(e) Ishida, K.; Ishibashi, M.; Shigemori, H.; Sasaki, T.;
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Hattori, T.; Adachi, K.; Shizuri, Y. J. Nat. Prod. 1997, 60,
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Borges, M. J. Nat. Prod. 1998, 61, 548–550.
2. Piers, E.; Livain, M. L.; Han, Y.; Plourde, G. L.; Guy, L.;
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966.
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6923–6926; (b) Iio, H.; Asao, K.; Tokoroyama, T. J.
Chem. Soc., Chem. Commun. 1985, 774–775.
Agelasine D is currently under testing for antimyco-
bacterial activity. Both agelasine F5d as well as sclareol14
(structure, see Scheme 1) are previously reported to be
active against Mycobacterium tuberculosis.
4. Asao, K.; Iio, H.; Tokoroyama, T. Tetrahedron Lett. 1989,
30, 6401–6404.
5. (a) Kobayashi, M.; Nakamura, H.; Wu, H.; Kobayashi, J.;
Ohizumi, Y. Arch. Biochem. Biophys. 1987, 259, 179–184;
(b) De Vries, D. J.; Sundar Rao, K.; Willis, R. H. Toxicon
1997, 35, 347–354; (c) Radeke, H. S.; Digits, C. A.;
Bruner, S. D.; Snapper, M. L. J. Org. Chem. 1997, 62,
2823–2831; (d) Mangalindan, G. C.; Talaue, M. T.; Cruz,
L. J.; Franzblau, S. G.; Adams, L. B.; Richardson, A. D.;
Ireland, C. M.; Conception, G. P. Planta Med. 2000, 66,
364–365.
Acknowledgements
The Norwegian Research Council is greatly acknowl-
edged for a Norwegian Government Scholarship to
B.T.U. as well as for partial financing of the Bruker
Avance instruments used in this study.
References andnotes
€
6. For conversion of sclareol to manool, see: Buchi, G.;
Biemann, K. Croat. Chem. Acta 1957, 29, 163–171.
7. Fujii, T.; Itaya, T. Heterocycles 1999, 51, 393–454, and
references cited therein.
1. (a) Nakamura, H.; Wu, H.; Ohizumi, Y.; Hirata, Y.
Tetrahedron Lett. 1984, 25, 2989–2992; (b) Wu, H.;

B. T. Utenova, L.-L. Gundersen / Tetrahedron Letters 45 (2004) 4233–4235
4235
8. Fujii, T.; Itaya, T.; Wu, C. C.; Tanaka, F. Tetrahedron
1971, 27, 2415–2423.
9. In solution, compound 1 mainly exists as the tautomer
shown in Scheme 2.
1H NMR (CHCl3, 300 MHz): d 0.64 (s, 3H, CH3), 0.76 (s,
3H, CH3), 0.83(s, 3H, CH 3), 0.93–2.38 (m, 16H), 1.76 (s,
3H, CH3), 3.72 (s, 3H, NCH3), 3.81 (s, 3H, OCH3), 4.44
(br s, 1H, CH2@), 4.79 (br s, 1H, CH2@), 5.03(br d, 2H, J
7.3Hz, CH 2), 5.36 (br t, 1H, J 7.3Hz, CH @), 7.68 (s, 1H),
7.76 (s, 1H); HRMS: found 452.3402, calcd for
C27H42N5Oþ 452.3383. Compound 4: Yield 278 mg
(27%) oil, as an 8:2 E/Z mixture. 1H NMR (CHCl3,
300 MHz, E-4 shown): d 0.57 (s, 3H, CH3), 0.71 (s, 3H,
CH3), 0.77 (s, 3H, CH3), 0.80–2.28 (m, 16H), 1.71 (s, 3H,
CH3), 3.76 (s, 3H, OCH3), 3.87 (s, 3H, NCH3), 4.41 (br s,
1H, CH2@), 4.65–4.71 (m, 3H), 5.34 (br t, 1H, J 5.8 Hz,
CH@), 7.75 (s, 1H, H-8), 8.41 (s, 1H, H-2); HRMS: found
452.3360, calcd for C27H41N5O 452.3383.
10. Synthesis of the bromide 1: A solution of PBr3 (0.33 mL,
3.5 mmol) in dry diethyl ether (5 mL) was added dropwise
to a stirred solution of (+)-manool (1.02 g, 3.5 mmol) and
pyridine (0.28 mL, 3.5 mmol) in dry diethyl ether (5 mL) at
)35 ꢁC. After stirring for 1 h at )35 ꢁC, the mixture was
diluted with diethyl ether (10 mL), extracted with 10% aq
HCl (5 mL) and satd aq NaHCO3 (2 · 5 mL), dried
(MgSO4), and evaporated in vacuo at ambient tempera-
ture to give the crude bromide 1; yield 1.06 g (85%) oil, E/
Z ratio: 85:15. E-1: 1H NMR (CHCl3, 300 MHz): d 0.66 (s,
3H, CH3), 0.78 (s, 3H, CH3), 0.81 (s, 3H, CH3), 1.1–2.4
(m, 16H), 1.70 (s, 3H, CH3), 4.00 (d, 2H, J 8.4 Hz, CH2),
4.47 (br s, 1H, CH2@), 4.81 (br s, 1H, CH2@), 5.48 (br t,
1H, CH@, J 8.4 Hz); Z-1: 1H NMR (CHCl3, 300 MHz): d
0.66 (s, 3H, CH3), 0.78 (s, 3H, CH3), 0.85 (s, 3H, CH3),
1.08–2.4 (m, 16H), 1.75 (s, 3H, CH3), 3.94 (d, 2H, J
8.4 Hz, CH2), 4.56 (br s, 1H, CH2@), 4.86 (br s, 1H,
CH2@), 5.48 (br t, 1H, CH@, J 8.4 Hz); HRMS found
355.1838, calcd for C20H3481Br [(M+H)þ] 355.1823.
11. For preparation of other primary allylic bromides from
tertiary allylic acetates employing TMS–Br/ZnI2, see:
Seltzman, H. H.; Moody, M. A.; Begum, M. K. Tetrahe-
dron Lett. 1992, 33, 3443–3446.
13. Synthesis of (+)-agelasine D: A mixture of the betaine 3
(138 mg, 0.31 mmol) and Zn powder (186 mg, 2.84 mmol)
in MeOH (5 mL), water (1 mL), and concd acetic acid
(0.2 mL) was stirred under argon at 60 ꢁC for 15 h. After
cooling, the mixture was filtered and the solid washed with
25 mL MeOH. The filtrate was mixed with MeOH
(10 mL), satd aq NaCl (1.5 mL), and water (10 mL) and
stirred for 1 h before evaporation. The residue was
dissolved in satd aq NaCl (5 mL) and water (5 mL),
extracted with CH2Cl2 (5 · 25 mL), dried (MgSO4), and
evaporated. The product was purified by flash chroma-
tography on silica gel eluting with CH2Cl2 followed by
CH2Cl2–MeOH (100:1), CH2Cl2–MeOH (40:1), and
12. Synthesis of the compounds 3 and 4: A mixture of
compound 1 (405 mg, 2.26 mmol) and the allylic bromide 2
(1.038 g, 2.94 mmol) in dry DMA (7 mL) was stirred at
50 ꢁC under argon for 21 h. The reaction mixture was
evaporated and the products were separated by flash
chromatography on silica gel eluting with CH2Cl2, fol-
lowed by EtOAc–EtOH–NH3 (aq) (160:5:2), EtOAc–
EtOH–NH3 (aq) (40:10:1), and CH2Cl2–MeOH–NH3
(aq) (35:5:1). Compound 3: Yield 636 mg (60%) as an E/
CH2Cl2–MeOH (4:1); yield 69 mg (51%), mp 128–130 ꢁC,
20
colorless crystals; ½aꢀ +9.4 (c 1.0, CH3OH); (lit.1a ½aꢀ
D
D
+10.4 (c 1.1, CH3OH). 1H NMR (CHCl3, 300 MHz): d
0.60 (s, 3H, Me), 0.74 (s, 3H, Me), 0.82 (s, 3H, Me), 0.7–
2.3 (m, 16H), 1.81 (s, 3H, Me), 4.05 (br s, 3H, NMe), 4.38
(br s, 1H), 4.74 (br s, 1H), 5.36 (br t, 1H, CH@, J 6.3Hz),
5.66 (br d, 2H, CH2, J 6.3Hz), 7.09 (br s, 2H, NH 2), 8.43
(s, 1H), 10.62 (s, 1H). HRMS: found 422.3263, calcd for
C26H40N5 422.3278. 13C NMR data were also in good
þ
Z mixture. Crystallization from EtOAc afforded 436 mg
agreement with those reported before.1a
14. Copp, B. Nat. Prod. Rep. 2003, 20, 535–557.
20
D
(43%) pure E-3, mp 195–197 ꢁC, ½aꢀ +23.8 (c 2, CHCl3).