N. Ullah, K. M. Arafeh / Tetrahedron Letters 50 (2009) 158–160
159
NH2.HCl
Pd-C, H2, 50 psi
NaCN, DMF
CN
OH
HO
HO
HO
ethanol, HCl, 12 h, 95%
130 ºC, 24 h, 65%
6
5
7
MeOH, Br2
60 ºC, 14 h.
quant.
O
O
SOCl2, THF
r.t., 14 h
Br
Br
H3CO
OH
Br
HO
NH2.HBr
Cl
H3CO
8
4
9
Br
i) THF, DMF
2,6-lutidine, 5 - 10 ºC
ii) 9, 1 h, 70%
Br
OCH3
Br
H
N
OCH3
Br
H
N
Br
Br
Br
O
Br
O
O
DMF, K2CO3, r.t., 20 h, 95%
HO
Br
11
Br
10
excess NH4OH, THF,
80 ºC, 8 h, 88%
Br
OCH3
H
N
Br
O
H2N
O
Br
aplysamine 6 (1)
Scheme 2. Synthesis of aplysamine 6 (1) from compounds 4 and 7.
of thionyl chloride in THF, and after evaporation of the solvents, a
solution of acid chloride 9 in dry THF was added dropwise to a
solution of dibromide 8 in THF at À10 °C using triethylamine as
base to afford a low yield (20%) of the desired amide 10, along with
the formation of a diacylated side product which made column
purification very tedious. The solubility of the dibromide 8 in
THF at À10 °C was very poor and hence in a second attempt, we
added the acid chloride 9 to a solution of dibromide 8 in a mixture
of THF and DMF (1:1) at 5–10 °C using 2,6-lutidine as the base and
this gave the desired amide 1010 cleanly in 70% yield after column
purification. The amide 10 was alkylated by the action of excess
1,3-dibromopropane in DMF using potassium carbonate as base
to give compound 11 in an excellent yield (95%), which in turn
was reacted with excess ammonium hydroxide at 80 °C for 8 h in
a sealed tube to produce aplysamine 6 (1) in an excellent yield
(88%) (Scheme 2). The spectral data of our synthetic 111 coincided
with those of the natural material.6
associated with this article can be found, in the online version, at
References and notes
1. Zhang, F. L.; Casey, P. J. Annu. Rev. Biochem. 1996, 65, 241–269.
2. Kloog, Y.; Cox, A. D. Semin. Cancer Biol. 2004, 14, 253–261.
3. Casey, P. J.; Seabra, M. C. J. Biol. Chem. 1996, 271, 5289–5292.
4. Winter-Vann, A. M.; Baron, R. A.; Wong, W.; Cruz, J. D.; York, J. D.; Gooden, D.
M.; Bergo, M. O.; Young, S. G.; Toone, E. J.; Casey, P. J. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 4336–4341.
5. Bergo, M. O.; Gavino, B. J.; Hong, C.; Beigneux, A. P.; McMahon, M.; Casey, P. J.;
Young, S. G. J. Clin. Invest. 2004, 113, 539–550.
6. Buchanan, M. S.; Carroll, A. R.; Fechner, G. A.; Boyle, A.; Simpson, M.; Addepalli,
R.; Avery, V. M.; Hooper, J. N. A.; Cheung, T.; Chen, H.; Quinn, R. J. J. Nat. Prod.
2008, 71, 1066–1067.
7. Lee, H. J.; Seo, J. W.; Lee, B. H.; Chung, K-H.; Chi, D. Y. Bioorg. Med. Chem. Lett.
2004, 14, 463–466.
8. Fernández-Martínez, E.; Bobadilla, R. A.; Morales-Ríos, M. S.; Muriel, P.; Pérez-
Álvarez, V. M. Med. Chem. 2007, 3, 475–479.
9. Schwartz, M. A.; Zoda, M.; Vishnuvajjala, B.; Mami, M. J. Org. Chem. 1976, 41,
2502–2503.
In conclusion, we have accomplished an efficient first total
synthesis of aplysamine 6 (1), an inhibitor of isoprenylcysteine
carboxy methyltransferase, in an overall 55% yield from 7 and 4.
10. Typical procedure for the synthesis of amide 10: To a solution of compound 4
(0.3 g, 1.17 mmol) in dry THF (10 mL) at 0 °C was added thionyl chloride
(0.42 g, 3.51 mmol) dropwise and the reaction was stirred overnight at room
temperature. The solvent was evaporated and the acid chloride 9 was kept
under high vacuum for 1 h. In another flask, a solution of compound 8 (0.45 g,
1.29 mmol) in a mixture of dry THF (15 mL) and DMF (15 mL) was cooled to
between 5 and 10 °C, followed by the dropwise addition of 2,6-lutidine (0.55 g,
5.16 mmol) and after being stirred for 0.5 h, a solution of 9 in dry THF (6 mL)
was added dropwise to the reaction mixture over the course of 15 min. The
reaction mixture was stirred for 1 h at the same temperature, then diluted with
ethyl acetate and washed successively with 2 N HCl, brine, sat. NaHCO3, and
brine and dried over sodium sulfate. Column chromatography of the dark
orange oily material, eluted with ethyl acetate:hexanes (4:6), afforded amide
10 as a white crystalline solid (0.43 g, 70%); mp: 172–173 °C. Anal. Calcd for
C18H16Br3NO3 requires C, 40.48; H, 3.02; N, 2.62. Found: C, 40.42; H, 3.06; N,
Acknowledgment
The authors gratefully acknowledge the generous materials
support from Dr. Shaikh Ashrof Ali.
Supplementary data
1H NMR and 13C NMR spectra of aplysamine 6 (1) and the 1H
NMR spectrum of compound 10 are available. Supplementary data
2.59. IR (KBr) (m
max/cmÀ1) 3415, 3250, 1675, 1530, 1485, 1245, 1150. 1H NMR