Asymmetric annulation toward pyrrolopip erazinones: Concise enantioselective syntheses of pyrrole alkaloid natural products

Article abstract of DOI:10.1021/ol070742y

A novel Pd-catalyzed asymmetric annulation between 5-bromopyrrole-2- carboxylate esters and vinyl aziridines has been developed to efficiently construct pyrrolopiperazinones, which can serve as key intermediates in the enantioselective syntheses of pyrrol

Full text of DOI:10.1021/ol070742y

ORGANIC
LETTERS
2007
Vol. 9, No. 12
2357-2359
Asymmetric Annulation toward
Pyrrolopiperazinones: Concise
Enantioselective Syntheses of Pyrrole
Alkaloid Natural Products
Barry M. Trost* and Guangbin Dong
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received March 26, 2007
ABSTRACT
A novel Pd-catalyzed asymmetric annulation between 5-bromopyrrole-2-carboxylate esters and vinyl aziridines has been developed to efficiently
construct pyrrolopiperazinones, which can serve as key intermediates in the enantioselective syntheses of pyrrole alkaloid natural products.
In this paper, the total synthesis of (−)-longamide B in five steps and the first total syntheses of agesamides A and B in six steps from 6 and
7 are reported.
Bromopyrrole alkaloids represent a large class of marine
natural products with various interesting biological proper-
ties.1 Pyrrolopiperazinone skeletons have been found in
numerous bromopyrrole alkaloids, such as longamide B (1),
longamide B methyl ester (2), hanishin (3), cyclooroidin (4),
and the agesamides (5). Longamide B, isolated from Agelas
dispar in racemic form, exibits antibiotic activity against
several strains of Gram-positive bacteria (MIC 50 µg/mL).2
Longamide B methyl ester, originally obtained from Homax-
inella and recently from Agelas ceylonica, displays cytotoxic
activity against P388 lymphocytic leukemia cells (ED50 30
µg/mL).3 Hanishin, the ethyl ester of longamide B, was
isolated from Acanthella carteri and shows cytotoxic activity
against NSCLC-N6 human non-small-cell-lung carcinoma
(IC50 9.7 µg/mL).4 No bioactivity has been found in (-)-
cyclooroidin from marine sponge Agelas oroides5 and no
activity study has been conducted on the newly isolated
agesamides A and B from Agelas species.6
Despite their interesting biological activities and chemical
structures, limited enantioselective syntheses of the above
(3) (a) Umeyama, A.; Ito, S.; Yuasa, E.; Arihara, S.; Yamada, T. J. Nat.
Prod. 1998, 61, 1433. (b) Srinivasa Reddy, N.; Venkateswarlu, Y. Biochem.
Syst. Ecol. 2000, 28, 1035.
(4) Mancini, I.; Guella, G.; Amade, P.; Roussakis, C.; Pietra, F.
Tetrahedron Lett. 1997, 38, 6271.
(5) Fattorusso, E.; Taglialatela-Scafati, O. Tetrahedron Lett. 2000, 41,
9917.
(6) Tsuda, M.; Yasuda, T.; Fukushi, E.; Kawabata, J.; Sekiguchi, M.;
Fromont, J.; Kobayashi, J. Org. Lett. 2006, 8, 4235.
(1) (a) Christophersen, C. In The Alkaloids; Brossi, A., Ed.; Academic
Press: Orlando, FL, 1985; Vol. 24, pp 25-98. (b) Hao, E.; Fromont, J.;
Jardine, D.; Karuso, P. Molecules 2001, 6, 130 and references therein.
(2) Cafieri, F.; Fattorusso, E.; Taglialatela-Scafati, O. J. Nat. Prod. 1998,
61, 122.
10.1021/ol070742y CCC: $37.00
© 2007 American Chemical Society
Published on Web 05/12/2007

Table 1. Selected Optimization Studiesa
entry
additives
yield,b %
ee,c %
1
2
3
10 mol % HOAc
50 mol % Cs2CO3
none
19 (28)d
41
72
71
89
95
a All reactions were performed with 1.05 equiv of 6 and 1.0 equiv of 7
at ambient temperature in DCM (0.1 M); DMB ) 2,4-dimethoxybenzyl.
b Isolated yield. c ee determined by chiral HPLC. d Parentheses indicate yield
based on recovered starting material (brsm).
Figure 1. Structures of longamide B (1), longamide B methyl ester
(2), hanishin (3), cyclooroidin (4), and agesamides (5).
bromopyrrole alkaloids have been reported.7 In this paper,
we report a new Pd-catalyzed asymmetric annulation between
5-bromopyrrole-2-carboxylate esters and vinyl aziridines to
give pyrrolopiperazinones, which serve as key intermediates
in the enantioselective syntheses of longamide B, longamide
B methyl ester, hanishin, cyclooroidin, and agesamides.
Recently, we have developed the use of pyrroles as
nucleophiles in the Pd-catalyzed AAA (asymmetric allylic
alkylation) reactions, and have successfully applied this
methodology in the total synthesis of agelastatin A.8 The
Pd-catalyzed dynamic kinetic asymmetric transformation
(DYKAT) of vinyl aziridines has been established with
isocyanates9 and several other nucleophiles.10 Aziridines are
usually less reactive toward nucleophilic additions, thus in
this scenario isocyanates not only act as nucleophiles but
also activate the aziridines to make it a better leaving group.
The extension of the DYKAT methodologies with the
combination of pyrroles and vinyl aziridines would poten-
tially provide valuable building blocks for the syntheses of
pyrrole alkaloids, and we envisioned that by using a
5-bromopyrrole-2-carboxylate: the nitrogen on the pyrrole
would behave as a good nucleophile to regioselectively open
the aziridine ring during the AAA, while the ester group on
the pyrrole would act as a nitrogen acceptor to form a
6-membered lactam. Therefore, the pyrrolopiperazinone
skeleton can be formed in one step.
and 7.5 mol % of (R,R)-L. A catalytic amount of HOAc has
been shown to greatly increase the enantioselectivity in the
Pd-catalyzed cycloadditions of isocyanates to vinyl aziri-
dines.9 By using 10 mol % of HOAc we obtained the desired
pyrrolopiperazinone 8 in 71% ee but very low yield due to
the decomposition of starting materials. Addition of 50 mol
% of Cs2CO3 gave much higher ee (89%) but slightly
improved yield (41%). However, to our surprise, without any
additives, the annulation product 8 was obtained in 72% yield
and 95% ee. The absolute configuration was assigned by
analogy to other reactions of substrate 7.11
With pyrrolopiperazinone 8 in hand, longamide B could
be synthesized in four steps (Scheme 1). Hydroboration of
8 with 9-BBN followed by oxidation with sodium perborate
gave primary alcohol 9 in high yield and excellent regio-
selectivity. Under optimized conditions, the DMB group was
cleaved by treating 9 with 5 equiv of tetrahydrothiophene
in TFA/DCM (1:1). Although the deprotection product was
contaminated with its protiodebrominated counterpart prod-
uct, the following NBS-mediated bromination afforded
dibromo alcohol 10 in 96% yield over two steps. Conditions
for oxidizing primary alcohol 10 to the carboxylic acid have
been screened, and the PCC-catalyzed oxidation with H5-
12
IO6 gave (S)-(-)-longamide B (1) in 63% (brsm 90%)
yield. A more effective oxidation was found later in an
attempt to oxidize 10 to the corresponding aldehyde. Surpris-
ingly, the treatment of 10 with 10 mol % of TEMPO and
2.5 equiv of PhI(OAc)2 in DCM13 produced carboxylic acid
1 instead of the aldehyde in 95% yield. The total synthesis
of (S)-(-)-longamide B also confirmed the absolute config-
uration of the Pd-catalyzed asymmetric annulation reaction.
According to Banwell et al.,7c longamide B methyl ester and
hanishin can be respectively accessed from longamide B in
Initial studies examined the reaction between methyl
5-bromopyrrole-2-carboxylate 6 and vinyl aziridine 711
(Table 1) in the presence of 2.5 mol % of [Pd(C3H5)Cl]2
(7) For the asymmetric syntheses of 1-4, see: (a) Patel, J.; Pelloux-
Le´on, N.; Minassian, F.; Valle´e, Y. J. Org. Chem. 2005, 70, 9081. (b) Patel,
J.; Pelloux-Le´on, N.; Minassian, F.; Valle´e, Y. Tetrahedron Lett. 2006, 47,
5561. For racemic syntheses of 1-4, see: (c) Banwell, M. G.; Bray, A.
M.; Willis, A. C.; Wong, D. J. New J. Chem. 1999, 23, 687. (d) Papeo, G.;
Go´mez-Zurita Frau, M. A.; Borghi, D.; Varasi, M. Tetrahedron Lett. 2005,
46, 8635. (e) Po˜verlein, C.; Breckle, G.; Lindel, T. Org. Lett. 2006, 8, 819.
(8) Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
(11) For the synthesis of aziridine 7, see: Trost, B. M.; Fandrick, D.
Org. Lett. 2005, 7, 823.
(12) Hunsen, M. Synthesis 2005, 2487.
(9) Trost, B. M.; Fandrick, D. J. Am. Chem. Soc. 2003, 125, 11836.
(10) Fandrick, D. Ph.D. Thesis, Stanford University, 2006.
(13) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
2358
Org. Lett., Vol. 9, No. 12, 2007

steps as a 1:1 mixture, and are spectroscopically identical
with those previous isolated.6
Scheme 1. Syntheses of (S)-Longamide B, Hanishin,
The mechanism of the Pd-catalyzed asymmetric alkyla-
tion-annulation between bromopyrrole 6 and vinyl aziridine
7 is outlined in Scheme 3. Both enantiomers of vinyl aziridine
Longamide B Methyl Ester, and Cyclooroidin
Scheme 3. Mechanism of the Asymmetric
Alkylation-Annulation
7 can be ionized by chiral Pd(0)L* and the hydrogen on the
pyrrole acts as a mild proton source to facilitate the ring-
opening. To obtain the asymmetric induction, the intercon-
version of the diastereomeric π-allyl palladium intermediates
12 and 13 via a π-σ-π sequence must occur faster than
the subsequent nucleophilic addition and be under Curtin-
Hammett conditions. The regioselectivity of the addtion can
be explained by the directing effect of the N-H-N hydrogen
bond.
one step, while cyclooroidin can be synthesized in four steps
from longamide B based on the work of Papeo et al.7d and
Pelloux-Le´on et al.7b Therefore, our route also constitutes
formal total syntheses of longamide B methyl ester (2),
hanishin (3), and cyclooroidin (4).
In conclusion, we have developed an enantioselective, Pd-
catalyzed alkylation-annulation reaction to construct a
pyrrolopiperazinone from a 5-bromopyrrole-2-carboxylate
ester and a vinyl aziridine. Application of this protocol leads
to the concise asymmetric synthesis of longamide B in five
steps from 6 and 7. We have also completed the first total
synthesis of agesamides A and B, which further demonstrates
the value of this methodology in the enantioselective
syntheses of pyrrole alkaloid natural products.
Agesamides A and B were isolated as a 1:1 epimeric
mixture from marine sponge Agelas (SS-1056),6 and to the
best of our knowledge no total synthesis has been reported
to date. Treatment of alcohol 10 with Dess-Martin periodane
(DMP) under buffered conditions gave the desired aldehyde
11, which was subsequently subjected to the Bucherer-Bergs
hydantoin formation protocol.14 To our delight, agesamides
A and B (5) were produced in quantative yield over two
Acknowledgment. We thank the National Institutes of
Health (GM33049) and the National Science Foundation for
their generous support of our programs. Mass spectra were
provided by the Mass Spectrometry Regional Center of the
University of California-San Francisco, supported by the
NIH Division of Research Resources. We also thank Dr.
Daniel Fandrick for a thoughtful discussion and vinyl
aziridine samples. G.D. is a Stanford Graduate Fellow.
Palladium salts were generally supplied by Johnson-Matthey.
Scheme 2. Synthesis of Agesamides A and B
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL070742Y
(14) Ware, E. Chem. ReV. 1950, 46, 403.
Org. Lett., Vol. 9, No. 12, 2007
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