it has average GI50 and LC50 values of 1.6 and 18 µM,
respectively.4a Certain tambjamines have also been observed
to bind duplex DNA and can cleave this biomolecule in the
presence of Cu(II).4a While the tambjamines have been
manipulated chemically for the purposes of securing a library
of analogues,6 they do not appear to have been the subject
of any total synthesis studies. Accordingly, we now report
the de novo preparation of all but three members of the class
using straightforward and unambiguous methods that have
permitted the confirmation of the structures of these com-
pounds. The present work should also allow for a more
comprehensive evaluation of the biological properties of
these intriguing alkaloids.
of acetic acid at 18-50 °C then afforded the acetate salts of
tambjamines 2-5 in yields ranging from 69 to 100%. For
example, treatment of aldehyde 16 with 1-aminododecane
under the specified conditions produced the acetate salt of
BE-18591 (5) in 100% yield. The spectral data derived from
this material matched those reported for the natural product.2c,10
Thus far, we have been unable to identify conditions under
which aldehyde 16 reacts with ammonia or a surrogate
thereof so as to provide useful quantities of tambjamine A
(1).
The unsaturated primary amine required for the preparation
of tambjamine 6 by the method just described has not been
reported in the literature but was readily generated by the
route outlined in Scheme 2. Thus, following a protocol
The route used in establishing total syntheses of tamb-
jamines 2-5 is shown in Scheme 1. This relies upon the
Scheme 2
Scheme 1
recently reported and very concise protocol of Lavalle´e and
co-workers7 for the synthesis of aldehyde 16, a pivotal but
previously difficult to access intermediate associated with
various syntheses of prodigiosin4 and a compound that is
also generated by base hydrolysis of the non-brominated
tambjamines.6 Thus, as reported by Lavalle´e and co-workers,7
commercially available 4-methoxy-3-pyrolin-2-one (13) was
subjected to a Vilsmeier-Haack reaction using POBr3 and
diethylformamide, and the ensuing azafulvene 14 (49%)
engaged in a Suzuki-Miyaura cross-coupling reaction8 with
the readily available boronic acid 159 to give the required
aldehyde 16 in 95% yield. Reaction of a solution of this last
compound in 1,2-dichloroethane (DCE) with the relevant
range of commercially available alkyl amines in the presence
reported by Bulkowski,11 the bis-tosyl derivative, 17, of
ethanolamine was treated with aqueous KOH to give
aziridine 1811 (96%) that was then subjected to nucleophilic
ring-opening with the anion derived from 1-decyne (19) using
a procedure reported by Gronquist and Meinwald.12 The
ensuing internal alkyne 20 (42%) was subject to hydrogena-
tion using Lindlar’s catalyst in the presence of quinoline13
so as to afford the Z-alkene 21 in 99% yield. Reductive
cleavage of the sulfonamide residue within this last com-
pound using sodium naphthalenide in 1,2-dimethoxyethane
(5) Tanigaki, K.; Sato, T.; Tanaka, Y.; Ochi, T.; Nishikawa, A.; Nagai,
K.; Kawashima, H.; Ohkuma, S. FEBS Lett. 2002, 524, 37.
(6) Davis, R. A.; Carroll, A. R.; Quinn, R. J. Aust. J. Chem. 2001, 54,
355.
(7) Dairi, K.; Tripathy, S.; Attardo, G.; Lavalle´e, J.-F. Tetrahedron Lett.
2006, 47, 2605.
(8) For a review of the palladium-catalyzed cross-coupling and related
reactions involving pyrroles see: Banwell, M. G.; Goodwin, T. E.; Ng, S.;
Smith, J. A.; Wong, D. J. Eur. J. Org. Chem. 2006, 3043.
(9) Martina, S.; Enkelmann, V.; Wegner, G.; Schlu¨ter, A.-D. Synthesis
1991, 613.
(10) We believe such comparisons are legitimate since it has been
reported (see ref 2d) that there is little difference between the NMR spectra
of various tambjamines and those of the corresponding acetate salts.
(11) Martin, A. E.; Ford, T. M.; Bulkowski, J. E. J. Org. Chem. 1982,
47, 412.
(12) Gronquist, M. R.; Meinwald, J. J. Org. Chem. 2001, 66, 1075.
(13) Overman, L. E.; Brown, M. J.; McCann, S. F. Org. Synth. 1989,
68, 182.
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Org. Lett., Vol. 9, No. 24, 2007