of the aromatic A ring and the presence/nature of the C2
appendage on the C-ring; the C11 hemiaminal or its
corresponding imine is conserved throughout. While many
of these natural products exhibit general toxicity and are
therefore not clinically useful, interest remains in analogues
of these alkaloids that might have improved therapeutic
windows.5,6 Extensive studies have demonstrated that the
presence of a C2 side chain is meritorious with respect to
antitumor activity, and removal of the ortho phenol reduces
cardiotoxicity resulting from presumed in vivo generation
of o-quinone imines.5b Efficient approaches that could readily
afford A-ring and C2 side chain analogues are therefore
valuable.
Our attention was drawn to the anthramycin alkaloids
because of the opportunities that they presented for us to
evaluate our recently described methodology for hetero-
cycle synthesis using pyridine ring-opening reactions.7 The
5-amino-2,4-pentadienamide motifs present in anthramycin
and the porothramycins (see 1-3) are close relatives of
Zincke aldehydes (5-amino-2,4-pentadienals), which are
readily available from the ring-opening of pyridinium salts
(4 f 5, Figure 2).8-10 In a previous report, we extended
these ring-opening reactions to include pyridines bearing
tethered nucleophiles; aniline nucleophiles led to indoles (6
f 7), and an amide derived from 3-(2-aminoethyl)pyridine
(8) delivered N-acylpyrroline 9.7 While previous syntheses
of the porothramycins by Fukuyama4a and Langlois4b have
wisely used glutamate-type chiral pool precursors, we sought
to develop a nonobvious approach beginning with a deriva-
tive of the commercially available unnatural amino acid
3-pyridylalanine that takes advantage of this pyridine to
pyrroline rearrangement that simultaneously introduces the
C2 side chain. Our expedient enantiospecific formal synthe-
ses of porothramycins A and B using a Zincke ring-opening
of 3-pyridylalanine derivative 10 is detailed in this paper.
Figure 2. Pyridinium ring-openings to form acyclic Zincke alde-
hydes, indoles, and dihydropyrroles relevant to the porothramycins.
A ) activating group.
(S)-3-Pyridylalanine methyl ester bis(hydrochloride) (11)
was acylated with 3-methoxy-2-nitrobenzoyl chloride (12);
both substances are commercially available.11 The ester
group of 13 was selectively reduced with sodium borohy-
dride. Activation of the pyridine with 2,4-dinitrochloroben-
zene proceeded in moderate yield to afford salt 14. Ring-
opening of this pyridinium salt bearing the free hydroxyl
group yielded only traces of the desired dihydropyrrole
product, in spite of the success of model reactions (see 8 f
9, Figure 2) in alcoholic solvents. A one-pot hydroxyl group
silylation/rearrangement proceeded uneventfully to afford
dihydropyrrole 15 in 55% yield; dry ethanol was required
for rearrangement without hydrolysis to the acyclic Zincke
aldehyde. Oxidation of the resulting unsaturated aldehyde
to the corresponding dimethyl amide (16) could be ac-
complished in a single step according to the underutilized
procedure of Gilman.12,13 Cleavage of the silyl ether
completed a formal synthesis of both porothramycins A and
B because 17 is an intermediate in the Langlois syntheses;4b
simple redox manipulations as prescribed would deliver
porothramycins A (2) and B (3) in two and three more steps,
respectively.
(5) For reviews of the pyrrolobenzodiazepinone antitumor antibiotics,
see: (a) Cipolla, L.; Araujo, A. C.; Airoldi, C.; Bini, D. Anti-Cancer Agents
Med. Chem. 2009, 9, 1–31. (b) Baraldi, P. G.; Bovero, A.; Fruttarolo, F.;
Preti, D.; Tabrizi, M. A.; Pavani, M. G.; Romagnoli, R. Med. Res. ReV.
2004, 4, 475–528. (c) Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.;
Reddy, G. S. K. Curr. Med. Chem. Anti-Cancer Agents 2002, 2, 215–254.
(d) Thurston, D. E.; Bose, D. S. Chem. ReV. 1994, 94, 433–465. (e) Hurley,
L. H.; Thurston, D. E. Pharm. Res. 1984, 52–59. For more general reviews
on small molecules that alkylate the minor groove of DNA, see: (f) Denny,
W. A. Curr. Med. Chem. 2001, 8, 533–544. (g) Reddy, B. S. P.; Sondhi,
S. M.; Lown, J. W. Pharmacol. Ther. 1999, 84, 1–111
.
(6) For selected reports of analogue synthesis, see: (a) Langlois, N.;
Andriamialisoa, R. Z. Heterocycles 1989, 29, 1529–1536. (b) Rojas-
Rousseau, A.; Langlois, N. Tetrahedron 2001, 57, 3389–3395. (c) Had-
jivassilenva, T.; Thurston, D. E.; Taylor, P. W. J. Antimicrob. Chemother.
2005, 56, 513–516
.
(7) Kearney, A. M.; Vanderwal, C. D. Angew. Chem., Int. Ed. 2006,
45, 7803–7806.
(8) (a) Zincke, T. Liebigs Ann. Chem. 1903, 330, 361–374. (b) Zincke,
T. Liebigs Ann. Chem. 1904, 333, 296–345. (c) Zincke, T.; Wurker, W.
Liebigs Ann. Chem. 1905, 338, 107–141. (d) Ko¨nig, W. J. Prakt. Chem.
1904, 69, 105–137
.
(9) For reviews, see: (a) Becher, J. Synthesis 1980, 589–612. (b)
Becher, J.; Finsen, L.; Winckelmann, I. Tetrahedron 1981, 37, 2375–
2378. (c) Cheng, W.-C.; Kurth, M. J. Org. Prep. Proced. Int. 2002, 34,
(11) Because of a temporary shortage of the amino acid ester 11 from
Aapptech, we purchased the corresponding amino acid and performed a
Fischer esterification to provide 11. Similarly, while acid chloride 12 is
commercially available from Aldlab Chemicals in 5 g quantities, a more
economical approach was to convert the inexpensive carboxylic acid to 12
ourselves.
587–608
.
(10) For our other work inspired by the Zincke ring-opening of pyridines,
see: (a) Steinhardt, S. E.; Silverston, J. S.; Vanderwal, C. D. J. Am. Chem.
Soc. 2008, 130, 7560–7561. (b) Michels, T. D.; Rhee, J. U.; Vanderwal,
C. D. Org. Lett. 2008, 10, 4787–4790. (c) Martin, D. B. C.; Vanderwal,
C. D. J. Am. Chem. Soc. 2009, 131, 3472–3473. (d) Steinhardt, S. E.;
(12) Gilman, N. W. Chem. Commum. 1971, 733–734
(13) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968,
90, 5616–5617
.
Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 7546–7547
.
.
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Org. Lett., Vol. 12, No. 13, 2010
Michels, Theo D.
