Total synthesis of dispyrin, purpurealidin E, and aplysamine-1

Article abstract of DOI:10.1248/cpb.56.1362

Bromotyrosine alkaloids dispyrin (1), purpurealidin E (2), and aplysamine-1 (3) isolated from marine sponge, were synthesized from commercially available tyramine (4) as a common starting material. The overall yield was 18%, 39%, and 22% for 1 from 4 in 5

Full text of DOI:10.1248/cpb.56.1362

1362
Notes
Chem. Pharm. Bull. 56(9) 1362—1363 (2008)
Vol. 56, No. 9
Total Synthesis of Dispyrin, Purpurealidin E, and Aplysamine-1
Makoto YOSHIDA and Kentaro YAMAGUCHI*
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University; 1314–1 Shido, Sanuki, Kagawa
769–2193, Japan. Received June 23, 2008; accepted June 30, 2008; published online July 7, 2008
Bromotyrosine alkaloids dispyrin (1), purpurealidin E (2), and aplysamine-1 (3) isolated from marine
sponge, were synthesized from commercially available tyramine (4) as a common starting material. The overall
yield was 18%, 39%, and 22% for 1 from 4 in 5 steps, 2 in 5 steps, and 3 in 6 steps, respectively.
Key words total synthesis; bromotyrosine alkaloid; marine sponge; dispyrin; purpurealidin E; aplysamine-1
Bromotyrosine alkaloids, well known as one of biologi- ethers 8 and 9 in moderate yields (Chart 1).
cally active substances, possess a wide range of biological
After deprotection of N-Boc function in 8 followed by
activities including anti Human immunodeficiency virus 1 coupling with a bromopyrrole 1121) the expected dispyrin (1)
(HIV-1) activity,1) anti methicillin-resistant Staphylococcus was smoothly afforded, and good accordance of the H- and
1
aureus (MRSA) activity,2) anti multidrug-resistant Myco- 13C-NMR data of dispyrin trifluoroacetate (1-TFA)22) with
bacterium tuberculosis activity,3) and anti-angiogenic ac- those of reported data12) were observed (Chart 2).
tivity.4) Because of these interesting activities, a number of
Deprotection of 7 with 10% HCl aq in MeOH to give pur-
synthetic studies on these alkaloids have been reported.5—11) purealidin E (2), followed by reductive N-methylation with
Dispyrin (1)12) isolated from Agelas dispar (Agelasidae) NaBH(OAc)3 and formalin into aplysamine-1 (3).23) Syn-
and purpurealidin E (2)13) isolated from Psammaplysilla thetic aplysamine-1 (3) and the hydrochloride salt of N-
purpurea (Verongiidae) contain a structural motif similar acetylpurpurealidin E (12-HCl)24) were spectroscopically
to aplysamine-1 (3)14,15) isolated from Pseudoceratina ver- identical with reported data13—15) (Chart 3).
roucosa (Aplysinellidae), a brominated phenol having a 3-di-
In conclusion, we succeeded in the first total synthesis of
methylamino-1-propane (Fig. 1), known as the histamine H3 dispyrin (1) and purpurealidin E (2), and the chemical con-
receptor antagonist.16) But to the best of our knowledge, syn- version of 2 to aplysamine-1 (3), from commercially avail-
thetic and biological studies on 1 and 2 have not been re- able tyramine as a common starting material. The overall
ported to date. In this paper we present first total synthesis of yield was 18%, 39%, and 22% for 1 from 4 in 5 steps, 2 in 5
dispyrin (1) and purpurealidin E (2), and the chemical con-
version of 2 to aplysamine-1 (3).
Results
These alkaloids were synthesized from commercially
available tyramine (4). Introduction of a bromine atom at 4
was carried out by treatment with tetrabutylammonium tri-
bromide (TBAT)17) in the presence of calcium carbonate
(CaCO3)18) after protection of the amino function as a Boc
group19) to give a monobromophenol 6.20) A dibromophenol
74) can be synthesized from 6 with the same condition.
Mono- and di-brominated phenol 6 and 7 were treated with
3-dimethylamino-1-propanol in the presence of p-TsCl and
benzyltriethylammonium chloride (BTAC) provided amino
Reagent and conditions: (a) Boc2O, MeOH, rt, 2 h, 98%; (b) TBAT, CaCO3,
CH2Cl2–MeOH (3 : 1), rt, 1 h, 77%; (c) TBAT, CaCO3, CH2Cl2–MeOH (3 : 1), rt, 1 h,
84%; (d) 3-dimethylamino-1-propanol, p-TsCl, BTAC, 20% NaOH aq, toluene rt, 4 d,
45% on 6, 63% on 7.
Chart 1. Synthesis of Brominated Tyrosine Derivatives
Reagent and conditions: (a) 10% HCl aq, MeOH, rt, 1 h, quant.; (b) 11, pyridine,
CHCl3, rt, 18 h, 54%; (c) CF3COOH, CH2Cl2–MeOH (3 : 1), rt, 1 h, quant.
Fig. 1. Structure of Dispyrin (1), Purpurealidin E (2), and Aplysamine-1
(3)
Chart 2. Synthesis of Dispyrin (1)
∗ To whom correspondence should be addressed. e-mail: yamaguchi@kph.bunri-u.ac.jp © 2008 Pharmaceutical Society of Japan

September 2008
1363
11) Ortlepp S., Sjoegren M., Dahlstroem M., Weber H., Eble R., Edrada
R., Thoms C., Schupp P., Bohlin L., Proksch P., Mar. Biotechnol., 9,
776—785 (2007).
12) Piña I. C., White K. N., Cabrera G., Rivero E., Crews P., J. Nat. Prod.,
70, 613—617 (2007).
13) Venkateswarlu Y., Venkatesham U., Rao M. R., J. Nat. Prod., 62,
893—894 (1999).
14) Isolation: Xynas R., Capon R. J., Aust. J. Chem., 42, 1427—1433
(1989).
15) Synthesis: Kigoshi H., Kanematsu K., Yokota K., Uemura D., Tetra-
hedron, 56, 9063—9070 (2000).
16) Swanson D. M., Wilson S. J., Boggs J. D., Xiao W., Apodaca R., Bar-
bier A. J., Lovenberg T. W., Carruthers N. I., Bioorg. Med. Chem. Lett.,
16, 897—900 (2006).
17) Kajigaeshi S., Kakinami T., Okamoto T., Nakamura H., Fujikawa M.,
Bull. Chem. Soc. Jpn., 60, 4187—4189 (1987).
Reagent and conditions: (a) 10% HCl aq., MeOH, rt, 1 h, 98%; (b) 37% HCHO aq.,
NaBH(OAc)3, MeOH, rt, 3 h, 55%. (c) Ac2O, CHCl3, pyridine, rt, 18 h, 70%; (d) 10%
HCl aq., MeOH, rt, 2 h, quant.
18) Flanagan J. H., Jr., Owens C. V., Romere J. E., Waddell E., Kahn S. H.,
Hammer R. P., Soper S. A., Anal. Chem., 70, 2676—2684 (1998).
19) Qin L., Tomislav R., Org. Process. Res. Dev., 11, 598—604 (2007).
20) Peter P., Michael S., Arch. Pharm. (Weinheim), 322, 477—482 (1989).
21) Kitamura C., Yamashita Y., J. Chem. Soc., Perkin Trans. 1, 1997,
1443—1447 (1997).
Chart 3. Synthesis of Purpurealidin E (2) and Aplysamine-1(3)
steps, and 3 in 6 steps, respectively.
References and Notes
1
22) The selected data of 1-TFA; IR (ATR): n 3303, 1673 cmꢀ1. H-NMR
1) Ross S. A., Weete J. D., Schinazi R. F., Wirtz S. S., Tharnish P.,
Scheuer P. J., Hamann M. T., J. Nat. Prod., 63, 501—503 (2000).
2) Kim D., Lee I. S., Jung J. H., Yang S.-I., Arch. Pharmacol. Res., 22,
25—29 (1999).
3) Encarnacion-Dimayuga R., Ramirez M. R., Luna-Herrera J., Pharm.
Biol., 41, 384—387 (2003).
4) Kotoku N., Tsujita H., Hiramatsu A., Mori C., Koizumi N., Kobayashi
M., Tetrahedron, 61, 7211—7218 (2005).
5) Guo Z.-W., Machiya K., Salamonczyk G. M., Sih C. J., J. Org. Chem.,
63, 4269—4276 (1998).
6) Nicolaou K. C., Hughes R., Pfefferkorn J. A., Barluenga S., Roecker
A. J., Chem. Eur. J., 7, 4280—4295 (2001).
7) Fetterolf B., Bewley C. A., Bioorg. Med. Chem. Lett., 14, 3785—3788
(2004).
8) Harburn J. J., Rath N. P., Spilling C. D., J. Org. Chem., 70, 6398—
6403 (2005).
9) Hayakawa I., Teruya T., Kigoshi H., Tetrahedron Lett., 47, 155—158
(2006).
(400 MHz, CD3OD): d 2.24 (2H, m), 2.79 (2H, t, Jꢁ7.3 Hz), 2.95 (6H,
s), 3.38 (2H, t, Jꢁ7.8 Hz), 3.48 (2H, t, Jꢁ7.3 Hz), 4.12 (2H, t, Jꢁ
5.8 Hz), 6.73 (1H, d, Jꢁ1.6 Hz), 6.90 (1H, d, Jꢁ1.6 Hz), 6.94 (1H, t,
Jꢁ8.5 Hz), 7.16 (1H, dd, Jꢁ8.5, 2.3 Hz), 7.44 (1H, d, Jꢁ2.3 Hz). 13C-
NMR (100 MHz, CD3OD): d 25.5, 35.5, 41.8, 43.7, 57.0, 67.4, 97.4,
112.8, 113.2, 114.7, 122.7, 127.5, 130.2, 134.5, 135.1, 154.6, 162.5.
ESI-MS: m/z 472, 474, 476 [MꢂH]ꢂ.
23) The selected data of synthetic 3; IR (ATR): No characteristic absorp-
tion. 1H-NMR (400 MHz, CD3OD): d 2.04 (2H, m), 2.29 (6H, s), 2.30
(6H, s), 2.53 (2H, t, Jꢁ8.1 Hz), 2.65 (2H, t, Jꢁ7.8 Hz), 2.73 (2H, t,
Jꢁ8.1 Hz), 4.02 (2H, t, Jꢁ6.2 Hz), 7.46 (2H, s). 13C-NMR (100 MHz,
CD3OD): d 29.0, 33.2, 45.3, 45.4, 57.5, 61.7, 72.6, 119.0, 134.1,
140.5, 152.8. ESI-MS: m/z 407, 409, 411 [MꢂH]ꢂ, 429, 431, 433
[MꢂNa]ꢂ.
24) The selected data of 12-HCl; IR (ATR): n 3319, 1678 cmꢀ1. 1H-NMR
(400 MHz, CD3OD): d 1.94 (3H, s), 2.31 (2H, m), 2.76 (2H, t, Jꢁ
7.2 Hz), 2.97 (6H, s), 3.39 (2H, t, Jꢁ7.2 Hz), 3.52 (2H, t, Jꢁ7.8 Hz),
4.12 (2H, t, Jꢁ5.7 Hz), 7.49 (2H, s). 13C-NMR (100 MHz, CD3OD): d
22.3, 26.4, 35.0, 41.6, 43.7, 57.1, 71.1, 118.8, 134.4, 140.4, 152.2,
173.6. ESI-MS: m/z 421, 423, 425 [MꢂH]ꢂ, 443, 445, 447 [MꢂNa]ꢂ.
10) Godert A. M., Angelino N., Woloszynska-Read A., Morey S. R.,
James S. R., Karpf A. R., Sufrin J. R., Bioorg. Med. Chem. Lett., 16,
3330—3333 (2006).