Synthesis of tetrahydropyrroloiminoquinone alkaloids based on electrochemically generated hypervalent iodine oxidative cyclization

Article abstract of DOI:10.1021/ol902566p

[Chemical equation presented] An approach to the synthesis of the tetrahydropyrroloiminoquinone alkaloids has been developed and applied to the preparation of N-1-βD-ribofuranosyltetrahydropyrroloiminoquinones. The strategy utilizes oxidative cyclization

Full text of DOI:10.1021/ol902566p

ORGANIC
LETTERS
2010
Vol. 12, No. 3
436-439
Synthesis of Tetrahydropyrroloiminoquinone
Alkaloids Based on Electrochemically
Generated Hypervalent Iodine Oxidative
Cyclization
Keisuke Inoue, Yuichi Ishikawa, and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio UniVersity,
Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
nisiyama@chem.keio.ac.jp
Received November 5, 2009
ABSTRACT
An approach to the synthesis of the tetrahydropyrroloiminoquinone alkaloids has been developed and applied to the preparation of N-1-ꢀ-
D-ribofuranosyltetrahydropyrroloiminoquinones. The strategy utilizes oxidative cyclization of aryl-methoxyamides by hypervalent iodine to
construct the quinoline framework shared by members of this alkaloid family. The hypervalent iodine oxidant is generated in situ by anodic
oxidation of iodobenzene.
Tetrahydropyrroloiminoquinone alkaloids are of marine
origin1 and have attracted the interest of synthetic and
biological groups owing to their unique structural features
(Figure 1) and a wide range of biological properties. Of
particular significance is the fact that these alkaloids
display cytotoxic activities against KB tumor cells,2a
L1210 (24: IC50 ) 0.25 µM, 25: IC50 ) 2.1 µM)2b and
doxorubicin-resistant L1210/DX murine lymphocytic leu-
kemia cells,2c the human colon tumor cell line HCT-116
(25: IC50 ) 17.1 µM),2d,e esophageal cancer cell line
Since the early reports describing the isolation and charac-
terization of discorhabdins3 and prianosins,4 a number of
congeners have been identified and synthetic investigations have
been carried out.1 In earlier efforts, we developed routes for
the synthesis of discorhabdin C,5 makaluvamines,6 and
isobatzellines5b,7 that involve construction of the pyrroloqui-
nolone intermediate A from the corresponding indol deriva-
tive B (Scheme 1), followed by introduction of an amine
(2) (a) Casapullo, A.; Cutignano, A.; Bruno, I.; Bifulco, G.; Debitus,
C.; Gomez-Paloma, L.; Riccio, R. J. Nat. Prod. 2001, 64, 1354. (b)
Be´ne´teau, V.; Pierre´, A.; Pfeiffer, B.; Renard, P.; Besson, T. Bioog. Med.
Chem. Lett. 2000, 10, 2231. (c) D’Ambrosio, M.; Guerriero, A.; Chiasera,
G.; Pietra, F.; Tato`, M. Tetrahedron 1996, 52, 8899. (d) Radisky, D. C.;
Radisky, E. S.; Barrows, L. R.; Copp, B. R.; Kramer, R. A.; Ireland, C. M.
J. Am. Chem. Soc. 1993, 115, 1632. (e) Barrows, L. R.; Radisky, D. C.;
Copp, B. R.; Swaffar, D. S.; Kramer, R. A.; Warters, R. L.; Ireland, C. M.
Anti-Cancer Drug Des. 1993, 8, 333. (f) Keyzers, R. A.; Arendse, C. E.;
Hendricks, D. T.; Samaai, T.; Davies-Coleman, M. T. J. Nat. Prod. 2005,
68, 506. (g) Copp, B. R.; Fulton, K. F.; Perry, N. B.; Blunt, J. W.; Munro,
M. H. G. J. Org. Chem. 1994, 59, 8233. (h) Lill, R. E.; Major, D. A.;
Blunt, J. W.; Munro, M. H. G.; Battershill, C. N.; McLean, M. G.; Baxter,
R. L. J. Nat. Prod. 1995, 58, 306.
WHCO-1 (20: IC50 ) 56 µM, 29: IC50 ) 38 µM, 31: IC50
)
1.6 µM),2f and human ovarian carcinoma Ovcar 3 implanted
in athymic mice,2d,e along with inhibition of topoisomerase
II,2d,e and antimicrobial activity.2g,h,3f
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1. (b) Faulkner, D. J.
Nat. Prod. Rep. 1998, 15, 113. (c) Faulkner, D. J. Nat. Prod. Rep. 1996,
13, 75. (d) Faulkner, D. J. Nat. Prod. Rep. 1995, 12, 223. (e) Faulkner,
D. J. Nat. Prod. Rep. 1993, 10, 497. (f) Faulkner, D. J. Nat. Prod. Rep.
1992, 9, 323. (g) Faulkner, D. J. Nat. Prod. Rep. 1990, 7, 269.
10.1021/ol902566p  2010 American Chemical Society
Published on Web 12/29/2009

African latrunculid sponge Strongylodesma aliwaliensis8
prompted us to reinvestigate new approaches to the synthesis
of these alkaloids. In recent studies exploring synthetic applica-
tions of electrochemical methodologies, we observed that
oxidative cyclization of aromatic compounds carrying a meth-
oxyamide side chain was promoted by an electrochemically
generated hypervalent iodine oxidant. These processes lead
to formation of functionalized quinolinone derivatives (Scheme
1).9 The oxidant generated in these reactions displayed a
reactivity profile that is comparable to that of phenyliodi-
ne(III)bistrifluoroacetate (PIFA).
The new approach we have devised for the construction of
the pyrroloiminoquinone structure involves the installation of
the pyrrole ring on an appropriately substituted quinoline D,
which is obtained by oxidation of a corresponding methoxya-
mide derivative C (Scheme 1). The crucial feature of this plan
is the selection of appropriate functional groups in starting
substrate C. To explore the new protocol, the arylpropanamide
4 was prepared by the route shown in Scheme 2. The sequence
Figure 1. Tetrahydropyrroloiminoquinone alkaloids.
Scheme 2. Synthesis of the Quinolinone Derivative (5)
residue by using a tandem Michael-reverse Michael process.
Assembly of the spirocyclic structure of discorhabdin C was
accomplished by employing an anodic oxidation of a
bromophenol precursor.5
Scheme 1. Synthetic Strategies
was initiated by reaction of the anion generated from 3-ben-
zyloxy-2-nitrotoluene 110 with diethyl oxalate, followed by
oxidative decarboxylation and esterification to give the arylac-
(4) (a) Kobayashi, J.; Cheng, J.-F.; Ishibashi, M.; Nakamura, H.;
Ohizumi, Y.; Hirata, Y.; Sasaki, T.; Lu, H.; Clardy, J. Tetrahedron Lett.
1987, 28, 4939. (b) Cheng, J.-F.; Ohizumi, Y.; Walchli, M. R.; Nakamura,
H.; Hirata, Y.; Sasaki, T.; Kobayashi, J. J. Org. Chem. 1988, 53, 4621.
(5) (a) Nishiyama, S.; Cheng, J.-F.; Tao, X. L.; Yamamura, S. Tetra-
hedron Lett. 1991, 32, 4151. (b) Tao, X. L.; Cheng, J.-F.; Nishiyama, S.;
Yamamura, S. Tetrahedron 1994, 50, 2017.
The recent isolation of glycoside containing members of the
tetrahydropyrroloiminoquinone alkaloid family from the South
(3) (a) Perry, N. B.; Blunt, J. W.; McCombs, J. D.; Munro, M. H. G. J.
Org. Chem. 1986, 51, 5476. (b) Blunt, J. W.; Calder, V. L.; Fenwick, G. D.;
Lake, R. J.; McCombs, J. D.; Munro, M. H. G.; Perry, N. B. J. Nat. Prod.
1987, 50, 290. (c) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Higa, T.;
Sakai, R. J. Org. Chem. 1988, 53, 4127. (d) Perry, N. B.; Weavers, R. T.
Aust. J. Chem. 1988, 41, 1571. (e) Munro, M. H. G.; Perry, N. B.; Blunt,
J. W. U. S. Patent 1988, 4, 731–366. (f) Perry, N. B.; Blunt, J. W.; Munro,
M. H. G. Tetrahedron 1988, 44, 1727.
(6) (a) Izawa, T.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1994,
35, 917. (b) Izawa, T.; Nishiyama, S.; Yamamura, S. Tetrahedron 1994,
50, 13593.
(7) Tao, X. L.; Nishiyama, S.; Yamamura, S. Chem. Lett. 1991, 1785.
(8) Keyzers, R. A.; Samaai, T.; Davies-Coleman, M. T. Tetrahedron
Lett. 2004, 45, 9415.
Org. Lett., Vol. 12, No. 3, 2010
437

etate ester 2 (71%, 3 steps).11 Exposure of 2 to BrCH2CO2tBu
pathway to afford the spiro tricyclic product 13 rather than
the corresponding iminoquinone 14. To introduce func-
tionality that would enable installation of the C-7 amine
side chain found in makaluvamine D (25, Scheme 5),
under basic conditions led to formation of the branched
t
succinate diester 3. Selective removal of the Bu ester moiety
in 3 generated the corresponding carboxylic acid, which is
transformed to amide 4 by reaction with MeONH3Cl.
The results of exploratory studies revealed that the yields
for the oxidative cyclization process were dependent on the
nature of the one carbon side-chains required for eventual
installation of the pyrrole ring (Scheme 2). Importantly,
compound 4, possessing a methoxycarbonyl group underwent
efficient cyclization to produce the quinolinone 5 when
subjected to both electrochemically generated hypervalent iodine
or PIFA. Despite having a similar structure, the corresponding
nitrile 6 generated the quinolinone 7 in respective yields of only
10 and 21% when treated with PIFA or the electrochemically
generated oxidant.
Scheme 5. Chemical Conversion of 11
The route for installation of the key pyrrole unit was
initiated by transformation of 5 to the corresponding dihy-
droquinoline 8 (72%) via borane reduction (Scheme 3). Boc
bromination of 11 was attempted. However, as a conse-
quence of the higher reactivity of the C-6 position,
treatment of 11 with NBS led to generation of the
undesired monobromo and dibromo products 15 and 16.
In the course of an exploratory study, it was found that
11 was oxidized by using Fremy’s salt13 to give the
R-diketone 17 (99%), which was ideally suited for
introduction of C-7 functionality. Exhaustive deprotection
of 17 led to formation of damirone C (20). Also, removal
of the N-5 Boc group in 17 under acidic conditions,
followed by methylation of the product 18, gave 19, which
served as late intermediate in previous syntheses of damirones
A (22) and B (21).14 In addition, amination of 20 provided
makaluvamine I (24).15 Finally, removal of the N-1 tosyl group
in 18 followed by coupling with tyramine hydrochloride yielded
makaluvamine D (25).
Our attention next turned to synthesis of glycoside
congeners. In addition to several varieties of antitumor
activity, biological activities of nucleoside-like derivatives
will be assessed. As a result of this potential, we initiated
studies to prepare glycosyl iminoquinones. Among other
strategies examined, coupling of 26, produced from 17, with
the known chloro-sugar 2716 in the presence of NaH and
18-Crown-6 in DMF was found to yield the desired glyco-
Scheme 3
.
Synthesis of Tetrahydropyrroloiminoquinone
Derivative (11)
protection of 8 produced 9 (98%), which upon selective
reduction with DIBAL-H, yielded aldehyde 10. Finally
reaction of 10 with Zn/AcOH, followed by treatment with
TsCl-NaH and catalytic hydrogenolysis, gave 11.12
To probe an alternative route, tandem oxidative cy-
clization of 12 (Scheme 4), containing a methoxy amide
Scheme 4. Synthetic Approach
(9) (a) Amano, Y.; Nishiyama, S. Tetrahedron Lett. 2006, 47, 6505.
(b) Amano, Y.; Inoue, K.; Nishiyama, S. Synlett 2008, 134. (c) Amano,
Y.; Nishiyama, S. Heterocycles 2008, 75, 1997.
(10) Beer, R. J. S.; Clarke, K.; Khorana, H. G.; Robertson, A. J. Chem.
Soc. 1948, 1605.
(11) Reference of oxidative homologation, see: Zhang, Q.; Peng, Y.;
Welsh, W. J. Heterocycles 2007, 71, 389.
(12) Similar stepwise reaction through the corresponding dimethylacetal,
see: Roberts, D.; Joule, J. A. J. Org. Chem. 1997, 62, 568.
(13) Similar conversion of an aryl ether or a phenol to the corresponding
R-diketone residue, see: (a) Moro-oka, Y.; Fukuda, T.; Iwao, M. Tetrahedron
Lett. 1999, 40, 1713. (b) Shishido, K.; Takata, T.; Omodani, T.; Shibuya,
M. Chem. Lett. 1993, 557.
(14) (a) Sadanandan, E. V.; Cava, M. P. Tetrahedron Lett. 1993, 34,
2405. (b) Roberts, D.; Venemalm, L.; Alvarez, M.; Joule, J. A. Tetrahedron
Lett. 1994, 35, 7857.
(15) Wang, H.; Al-Said, N. H.; Lown, J. W. Tetrahedron Lett. 1994,
35, 4085.
side chain, was attempted. When submitted to hypervalent
iodine oxidation, 12 reacted by an entirely different
(16) Wilcox, C. S.; Otoski, R. M. Tetrahedron Lett. 1986, 27, 1011.
438
Org. Lett., Vol. 12, No. 3, 2010

Scheme 6
.
Conversion to Natural Products
Scheme 7. Synthesis of Glycosidic Derivatives
sides 28-ꢀ and 28-r in 50% yield as a 23:2 mixture (1H
NMR integration) along with unreacted 26 (ca. 50% yield).
The presence of a ꢀ-glycosidic linkage in 28-ꢀ was unam-
biguously demonstrated by using NOE techniques. The TBS-
protecting group in 28-ꢀ was smoothly removed by using
TFA to afford N-1-ꢀ-D-ribofuranosyldamirone C (29), along
with its R-anomer in a 100:1 ratio determined by the same
manner as described above. Another target, N-1-ꢀ-D-
ribofuranosylmakaluvamine I (31) was obtained by am-
monolysis of 29 with NH3 in MeOH. Spectroscopic data for
the synthetic iminoquinone glycosides matched those previ-
ously reported.8
ribofuranosyldamirone C (29) and N-1-ꢀ-D-ribofuranosyl-
makaluvamine I (31).
Acknowledgment. This work was supported by financial
support from the Scientific Research C and High-Tech
Research Center Project for Private Universities Matching
Fund (2006-2011) and from MEXT.
In conclusion, a key intermediate in synthetic routes for
preparation of members of the tetrahydropyrroloimino-
quinone alkaloid family was generated by using a novel
quinolinone synthetic methodology, involving oxidative
cyclization of an aryl-methoxyamide precursor promoted by
electrochemically generated hypervalent iodine species. This
effort has led to the first total syntheses of N-1-ꢀ-D-
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902566P
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