141.3, 141.4, 159.8; MS (ES) m/z 550 ([M + H]+), 444 (100); HRMS (ES)
(Scheme 4). The reason for such low yields is yet under
investigation in our laboratory but it is likely to be an issue of
pseudo-dimerisations through Diels–Alder type cycloadditions
involving 14 and its direct precursor 13.13
calcd for C36H39NO4H+: 550.2919, found: 550.2921.
1 L. Garrido, E. Zub´ıa, M. J. Ortega and J. Salva´, J. Org. Chem., 2003,
68, 293.
With compound 14 obtained in too little amounts, it was
decided to try out different types of oxidative conditions applied to
product 12 in order to see if the desired C8–C9 coupling can take
place despite high constraint resulting from the pyridinium’s
planarity. The outcome of such reactions is still under investigation
in our laboratory.
2 N. D. Smith, J. Hayashida and V. H. Rawal, Org. Lett., 2005, 7, 4309.
3 M. A. Grundl and D. Trauner, Org. Lett., 2006, 8, 23.
4 P. Wipf and M. Furegati, Org. Lett., 2006, 8, 1901.
5 P. S. Baran and N. Z. Burns, J. Am. Chem. Soc., 2006, 128, 3908.
6 J. H. Jeong and S. M. Weinreb, Org. Lett., 2006, 8, 2309.
7 It is known that the oxidation of L-phenylalanine to L-meta-tyrosine
mostly results from the attack of hydroxyl free radical: H. Kaur,
I. Fagerheim, M. Grootveld, A. Puppo and B. Halliwell, Anal.
Biochem., 1988, 172, 360.It has also been reported that tyrosine-
hydroxylase may produce small amounts of L-meta-tyrosine (as well as
L-para-tyrosine and L-DOPA of course) from L-phenylalanine:
M. H. Fukami, J. Haavik and T. Flatmark, Biochem. J., 1990, 268,
525; J. H. Tong, A. D’Iorio and N. L. Benoiton, Biochem. Biophys. Res.
Commun., 1971, 44, 229.
8 The peculiar L-meta-tyrosine pattern has been described in very few
natural products such as pacidamycins: R. H. Chen, A. M. Buko,
D. N. Whittern and J. B. McAlpine, J. Antibiot., 1993, 42, 512;
P. B. Fernandes, R. N. Swanson, D. J. Hardy, C. W. Hanson, L. Cohen,
R. R. Rasmussen and R. H. Chen, J. Antibiot., 1989, 42, 521;
J. P. Karwowski, M. Jackson, R. J. Theriault, R. H. Chen, G. J. Barlow
and M. L. Maus, J. Antibiot., 1989, 42, 506 and mureidomycins:
F. Isono, Y. Sakaida, S. Takahashi, T. Kinoshita and M. Inukai,
J. Antibiot., 1993, 46, 1203; F. Isono, M. Inukai, S. Takahashi,
T. Haneishi, T. Kinoshita and H. Kuwano, J. Antibiot., 1989, 42, 667;
F. Isono, T. Katayama, M. Inukai and T. Haneishi, J. Antibiot., 1989,
42, 674; K. Isono, J. Antibiot., 1988, 41, 1711; M. Inukai, F. Isono,
S. Takahashi, R. Enokita, Y. Sakaida and T. Haneishi, J. Antibiot.,
1989, 42, 662.
9 G. M. Keseru and M. Nogradi, Natural Products by Oxidative
Coupling, Biosynthesis and Synthesis, in Studies in Natural Products
Chemistry, ed. Atta-Ur-Rahman, Elsevier Science B. V., Amsterdam,
1998, vol. 20 (part F), pp. 263–322.
10 R. L. Franck and R. P. Seven, J. Am. Chem. Soc., 1949, 71, 2629.
11 For examples of ytterbium triflate used as a Lewis acid see this review
article: S. Luo, L. Zhu, A. Talukdar, G. Zhang, X. Mi, J.-P. Cheng and
P. G. Wang, Mini-Rev. Org. Chem., 2005, 2, 177 and other selected
examples: K. Manabe, D. Nobutou and S. Kobayashi, Bioorg. Med.
Chem., 2005, 13, 5154; N. Sakai, D. Aoki, T. Hamajima and
T. Konakahara, Tetrahedron Lett., 2006, 47, 1261; L.-M. Wang,
Y.-H. Wang, H. Tian, Y.-F. Yao, J.-H. Shao and B. Liu, J. Fluorine
Chem., 2006, 127, 1570.
In conclusion, we have proposed a new detailed biogenetic
hypothesis for haouamines that has led us to successfully achieve
the first steps of the first biomimetic total synthesis of haouamine
A. An advanced biomimetic precursor of that compound has been
obtained through a convenient and efficient multicomponent
reaction and the final two bonds that are needed to complete the
synthesis are currently being investigated in our laboratory. The
described biosynthetic hypothesis can serve as a useful framework
from which to develop a coherent and straightforward synthetic
plan towards haouamines (as well as close analogs such as
compounds 11, 12, 14) that competes with other synthetic
approaches. This example also contributes to demonstrate the
power of biomimetically inspired strategies in total synthesis.14
Notes and references
{ It is interesting to note that oxidative conditions under which radicals can
be generated on phenols to make phenolic couplings possible may also
generate free hydroxyl radicals responsible for the formation of L-meta-
tyrosine involved in our biogenetic proposal.
§ Compound 11: orange oil; Rf 5 0.40 (silica gel, CH2Cl2–MeOH 9 : 1); IR
(film, CHCl3): nmax 5 2937, 1585, 1260, 1030 cm21; 1H NMR (400 MHz,
CDCl3), d 1.25 (2 H, s), 3.27 (2 H, t, J 5 6.5 Hz), 3.67 (6 H, s), 3.86 (6 H, s),
5.15 (2 H, t, J 5 6.5 Hz), 6.55–7.45 (16 H, m), 8.47 (1 H, s), 8.75 (1 H, s);
13C NMR (100 MHz, CDCl3), d 29.6, 37.8, 55.1, 55.7, 63.5, 112.5, 113.5,
114.2, 116.6, 118.2, 119.6, 121.1, 122.6, 130.2, 130.8, 134.0, 136.9, 139.8,
140.5, 141.3, 160.2, 160.6; MS (ES) m/z 546 (M+), 440 (10), 426 (100);
HRMS (ES) calcd for C36H36NO4+: 546.2639, found: 546.2642.
" Compound 12: brown varnish; Rf 5 0.30 (silica gel, CH2Cl2–MeOH 85 :
15); IR (film, CH3OH): nmax 5 3061, 2926, 1589, 1029 cm21 1H NMR
;
12 L.-B. Yu, D. Chen, J. Li, J. Ramirez, P. G. Wang and S. G. Bott, J. Org.
Chem., 1997, 62, 208; B. B. Snider and B. J. Neubert, Org. Lett., 2005, 7,
2715.
(400 MHz, CD3OD), d 1.25 (2 H, s), 3.35 (2 H, t partially hidden by
CD3OD signal, J y 6.6 Hz), 4.97 (2 H, t, J 5 6.6 Hz), 6.55–7.45 (16 H, m),
8.78 (1 H, s), 8.88 (1 H, s); 13C NMR (100 MHz, CD3OD), d 30.8, 38.4,
64.4, 115.4, 115.6, 117.0, 117.2, 118.4, 119.7, 121.1, 121.3, 131.3, 131.9,
136.0, 138.5, 141.5, 141.9, 142.8, 159.3, 159.8; MS (ES) m/z 490 (M+), 398
(10), 384 (100); HRMS (ES) calcd for C32H28NO4+: 490.2013, found:
490.2015.
I Compound 14: yellow varnish; Rf 5 0.70 (silica gel, CH2Cl2–MeOH
95 : 5); IR (film, CHCl3): nmax 5 3010, 1579, 1300, 1108 cm21; 1H NMR
(400 MHz, CDCl3), d 2.52 (2 H, d, J 5 12 Hz), 2.75–3.10 (7 H, m), 3.25
(1 H, d, J 5 14.5 Hz), 3.82 (12 H, m), 6.26 (1 H, s), 6.75–7.30 (16 H, m);
13C NMR (100 MHz, CDCl3), d 30.2, 39.5, 40.1, 55.3, 58.9, 62.6, 66.0,
111.2, 111.4, 113.2, 114.4, 117.4, 117.8, 117.9, 128.5, 129.4, 129.7, 139.8,
13 K. Jakubowicz, Y.-S. Wong, A. Chiaroni, M. Be´ne´chie and
C. Marazano, J. Org. Chem., 2005, 70, 7780 and references cited therein.
14 For recent examples of biomimetic total syntheses and synthetic
approaches of complex polycyclic molecules in the alkaloid series, see
inter alia: E. Gravel, E. Poupon and R. Hocquemiller, Org. Lett., 2005,
7, 2497; C. H. Ge, S. Hourcade, A. Ferdenzi, A. Chiaroni, S. Mons,
B. Delpech and C. Marazano, Eur. J. Org. Chem., 2006, 18, 4106;
J. Sperry and C. J. Moody, Chem. Commun., 2006, 22, 2397; P. S. Baran,
B. D. Hafensteiner, N. B. Ambhaikar, C. A. Guerrero and
J. D. Gallagher, J. Am. Chem. Soc., 2006, 128, 8678.
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