Total syntheses of the marine pyrrole alkaloids polycitone A and B

Article abstract of DOI:10.1021/ol026555b

equation presented Polycitone B (2) was obtained in four steps from pyrrole dicarboxylic acid 3, including Friedel-Crafts reaction of the corresponding acid chloride with anisole. The conversion of 2 into polycitone A (1) was achieved in two steps via Mit

Full text of DOI:10.1021/ol026555b

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3287-3288
Total Syntheses of the Marine Pyrrole
Alkaloids Polycitone A and B
Andreas T. Kreipl, Caroline Reid, and Wolfgang Steglich*
Chemie Department, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13 (Haus F), D-81377 Mu¨nchen, Germany
wos@cup.uni-muenchen.de
Received July 18, 2002
ABSTRACT
Polycitone B (2) was obtained in four steps from pyrrole dicarboxylic acid 3, including Friedel−Crafts reaction of the corresponding acid
chloride with anisole. The conversion of 2 into polycitone A (1) was achieved in two steps via Mitsunobu alkylation of the pyrrolic NH group.
The synthesis of polycitone A proceeds in 18% overall yield and offers the possibility of varying the substituents on the pyrrole ring.
The polycitones A and B (1 and 2 respectively) are
polybrominated pyrrole alkaloids and were isolated by
Kashman and co-workers1,2 from marine ascidians of the
genus Polycitor. Polycitone A was found to be a potent
inhibitor of retroviral reverse transcriptases (i.e., human
immundeficiency virus type 1) and cellular DNA poly-
merases.3 In a continuation of our studies on the biomimetic
synthesis of marine 3,4-diarylpyrrole alkaloids,4 we now
report the first total syntheses of the polycitones A and B.
Our syntheses commence with dicarboxylic acid 3 used
previously for the preparation of polycitrin A.5 Compound
3 is easily obtained in 72% yield by oxidative coupling of
(1) Rudi, A.; Goldberg, I.; Stein, Z.; Frolow, F.; Benayahu, Y.; Schleyer,
Figure 1.
M.; Kashman, Y. J. Org. Chem. 1994, 59, 999-1003.
(2) Rudi, A.; Evan, T.; Aknin, M.; Kashman, Y. J. Nat. Prod. 2000, 63,
832-833.
(3) Loya, S.; Rudi, A.; Kashman, Y.; Hizi, A. Biochem. J. 1999, 344,
the dianion of 3-(4-methoxyphenyl)pyruvic acid and cycliza-
tion of the resulting 1,4-dicarbonyl intermediate with am-
monia. Treatment of dicarboxylic acid 3 with oxalyl chloride
followed by removal of the solvent and rigorous drying
yielded the crude acid chloride 4, which reacted with anisole
85-92.
(4) Lycogalic acid A: Fro¨de, R.; Hinze, C.; Josten, I.; Schmidt, B.;
Steffan, B.; Steglich, W. Tetrahedron Lett. 1994, 1689-1690. Polycitrin
A: Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995, 51, 9941-
9946. Lamellarins: (a) Heim, A.; Terpin, A.; Steglich, W. Angew. Chem.
1997, 109, 158-159; Angew. Chem., Int. Ed. Engl. 1997, 36, 155-156.
(b) Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J. 2000, 6, 1147-
1152. Storniamide A nonamethyl ether: Ebel, H.; Terpin, A.; Steglich, W.
Tetrahedron Lett. 1998, 39, 9165-9166. Purpurone, ningalin C: Peschko,
C.; Steglich, W. Tetrahedron Lett. 2000, 41, 9477-9481.
(5) Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995, 51, 9941-
9946.
10.1021/ol026555b CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/22/2002

under Friedel-Crafts conditions to afford the diketone 5 in
66% yield (Scheme 1). Surprisingly, this convenient method
Scheme 2. Synthesis of Polycitone Aa
Scheme 1. Synthesis of Polycitone Ba
a Reagents and conditions: (a) (COCl)2, DMF (cat.), CH2Cl2, 0
°C, 2 h; (b) AlCl3, PhOMe, CH2Cl2, rt, 12 h; (c) AlI3 (freshly
prepared from Al powder and I2), n-Bu4N+I-, PhH, reflux, 12 h;
(d) Br2, AcOH, rt, 48 h.
a Reagents and conditions: (a) AcCl (10 equiv), NEt3 (6 equiv),
CH2Cl2, rt, 12 h; (b) 2-(4-acetoxyphenyl)ethanol (4 equiv), PPh3
(4 equiv), DEAD (4 equiv), dry THF, reflux, 2 h; (c) N2H4‚H2O
(20 equiv), dry MeOH, rt, 45 min.
for the synthesis of a 2,5-dibenzoylpyrrole6 from the corre-
sponding pyrrole dicarboxylic acid chloride7 has not been
used before.
mild conditions with hydrazine monohydrate in dry metha-
nol10 to give polycitone A (1), as a yellow solid, in 88%
yield. Whereas the free phenol 1 exhibited small differences
from the reported 13C NMR data for the natural product, the
data of the permethyl derivative1 obtained from synthetic 1
by treatment with Me2SO4 and K2CO3 were in complete
agreement.
In summary our synthesis afforded polycitone A in eight
steps and 22% overall yield from 3-(4-methoxyphenyl)-
pyruvic acid. The synthesis is very flexible and can be easily
adapted to the preparation of analogues. Attempts to shorten
our syntheses by oxidative coupling of benzylic 1,2-diketones
and subsequent cyclization with ammonia or amines to 2,5-
dibenzoylpyrroles have been unsuccessful.
Attempted cleavage of the methoxy groups with BBr3,
AlBr3, EtSNa, or pyridine hydrochloride gave only partially
demethylated products. These difficulties were solved by
8
using freshly prepared AlI3 in the presence of n-Bu4N+I-
as a phase transfer catalyst.9 The resulting tetraphenol 6 was
then brominated in acetic acid at room temperature to provide
1
polycitone B (2) in 83% yield. The H NMR data derived
from the synthetic material were in close correspondence
with those reported in the literature.2 The chemical shifts in
the 13C NMR spectra exhibited small differences that may
be explained by solvent effects.
For the synthesis of polycitone A (1) (Scheme 2),
polycitone B (2) was converted into the tetraacetate 7, which
upon treatment with 2-(4-acetoxyphenyl)ethanol under Mit-
sunobu conditions in refluxing THF afforded peracetylpoly-
citone A (8) in 64% yield after purification by column
chromatography (in contrast, unbrominated analogues of
compound 7 could be alkylated already at room temperature
and provided the corresponding N-alkyl derivatives in much
better yields). The acetyl groups in 8 were removed under
Acknowledgment. We gratefully acknowledge the fi-
nancial support by the Fonds der Chemischen Industrie. C.R.
was on exchange from the University of Glasgow supported
by the ERASMUS program.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(6) Synthesis of a 2,3-dibenzoylpyrrole: Barik, R.; Kumar, C. V.; Das,
P. K.; George, M. V. J. Org. Chem. 1985, 50, 4309-4317.
(7) Gale, P. A.; Camiolo, S.; Chapman, C. P.; Light, M. E.; Hursthouse,
M. B. Tetrahedron Lett. 2001, 5095-5098.
(8) Bhatt, M. V.; Babu, J. R. Tetrahedron Lett. 1984, 25, 3497-3501.
(9) Andersson, S. Synthesis 1985, 436-437.
OL026555B
(10) Steglich, W.; Zechlin, L. Chem. Ber. 1978, 111, 3939-3948.
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Org. Lett., Vol. 4, No. 19, 2002