Aplidium Haouarianum Collected Off Tarifa Island (Cádiz Spain)
Progress Toward the Total Synthesis of Haouamine A
OH OH
OH
OH N H
Markus Furegati 9/17/2005 University of Pittsburgh @ Wipf group Foto © MLSSA 2002 Markus Furegati @ Wipf Group 1 9/17/2005 OH OH OH OH
OH OH
OH OH N HO N H H
Haouamine A Haouamine B
• New class of alkaloid isolated from speciemen of the tunicate Aplidium haouarianum collected off Tarifa Island (Cádiz Spain). • Haouamine A shows a high and selective activity against the HT-29 human colon carcinoma cell line with IC50 = 0.1 µg/ml (200 nM). • Structural feature: polyphenol, highly strained 3-aza-[7]-paracyclophane moiety
L. Garrido, E. Zubía, M. J. Ortega, J. Salvá „Haouamines A and B: A New Class of Alkaloids from the Ascidian Aplidium haouarianum“, JOC 2003, 68, 293-299. Foto © MLSSA 2002 Markus Furegati @ Wipf Group 2 9/17/2005 What‘s a Tunicate?
Kingdom Animalia sometimes known as tunicata and commonly called urochordates, sac-like marine filter feeders, they are tunicates or sea squirts characterized by a tough outer "tunic" Phylum Chordata made of the polysaccharide tunicin whilst other tunicates are much less robust. Subphylum Urochordata Whilst adults are sessile (immobile), larvae resemble tadpoles and swim up Class Ascidiacea and down in their marine environment.
Order Enterogona Suborder Aplousobranchia Family Polyclinidae
Genus Aplidium
Species Haouarianum (Pérès 1956)
Aplidium elegans (Giard, 1872) Foto taken from: www.ascidiacea.com
Markus Furegati @ Wipf Group 3 9/17/2005 Characterization of Haouamine A
• white solid, decomposition at 170°C 27 • [α] D= - 52.0 (c = 0.4, MeOH) 1 • H-NMR (600 MHz, acetone-d6)
13 • C-NMR (125 MHz, acetone-d6) -> 2 components with similar structure in a 2:1 ratio (slow pyramidal inversion at the bridgehead amine or atropisomerism)
L. Garrido, E. Zubía, M. J. Ortega, J. Salvá „Haouamines A and B: A New Class of Alkaloids from the Ascidian Aplidium haouarianum“, JOC 2003, 68, 293-299.
Markus Furegati @ Wipf Group 4 9/17/2005 Characterization of Haouamine A
• 1H-13C HMBC correlations:
• HRMS (CI) m/z 489.1909 [M+]
calcd for C32H27NO4, 489.1940 (6 ppm) • X-ray analysis, Mo-Kα (λ = 0.71073 Å), 100 K, crystals from MeOH
OH OH
OH
OH N H
1a
L. Garrido, E. Zubía, M. J. Ortega, J. Salvá „Haouamines A and B: A New Class of Alkaloids from the Ascidian Aplidium haouarianum“, JOC 2003, 68, 293-299.
Markus Furegati @ Wipf Group 5 9/17/2005 Biosynthesis of Haouamine A?
Tyrosine does not match, loss of hydroxyl group? Unknown amino acid precursor? -> no explanation
OH OH OH OH ? OH OH HO C OH OH N N H L-Tyrosine H
1a
L. Garrido, E. Zubía, M. J. Ortega, J. Salvá „Haouamines A and B: A New Class of Alkaloids from the Ascidian Aplidium haouarianum“, JOC 2003, 68, 293-299.
Markus Furegati @ Wipf Group 6 9/17/2005 Synthesis of 2-Aza-[7]-Paracyclophane
I- N +N N NaNH2, NH3 (l) [2,3] / 1,2-shift N+ + 11 -
48% 21% B. Hasiak et al. THL 1990, 31, 5769.
OH OH
OH 3-aza-[7]-paracyclophane OH N -> not applicable H
1a
Markus Furegati @ Wipf Group 7 9/17/2005 Published contributions
OH OH OR OR
OH OR
OH X N N Y
OR 1a
1) pyrrolidine OMe OMe O HO 1) dimethyl dicarbonate PhH, reflux O O TEA, DCM 2) 3-methoxybenzyl- 2) Swern, ox chloride, ACN NBS, ACN N N H ·HCl N N 96% 58% 99% O OMe Br O OMe O OMe
OMe IBX, DMSO 95% OMe OMe OMe OMe OMe OMe 1) MgBr OMe OMe OMe CuBr·DMS, -78°C OMe CF3SO3H MgBr O 2) PhSeCl O DCM HO THF 3) H2O2 N 71% N 68% N 57% N Br Br Br Br O OMe O OMe O OMe O OMe
N. D. Smith, J. Hayashida, V. H. Rawal „Facile Synthesis of the Indeno-Tetrahydropyridine Core of Haouamine A“ OL ASAP, Web Release Date: August 27, 2005.
Markus Furegati @ Wipf Group 8 9/17/2005 Acknowledgment Prof. Peter Wipf Wipf Group Members
Members of the NMR, MS, Xray Facilities $ Swiss National Science Foundation $
Markus Furegati @ Wipf Group 9 9/17/2005