Total synthesis of (±)-calcaridine A and (±)-epi-calcaridine A

Article abstract of DOI:10.1021/ol802018r

(Chemical Equation Presented) The first total synthesis of the Leucetta alkaloid calcaridine A is described based on a biosynthetic postulate. Application of an oxidative rearrangement of a 4,5-disubstituted imidazole leads to the formation of both calcaridine A and epi-calcaridine A. An X-ray crystal structure determination on the latter has allowed the assignment of the relative configuration of the epimeric natural product and calcaridine A by extrapolation.

Full text of DOI:10.1021/ol802018r

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5055-5058
Total Synthesis of (()-Calcaridine A and
(()-epi-Calcaridine A
Panduka B. Koswatta, Rasapalli Sivappa, H. V. Rasika Dias, and Carl J. Lovely*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Arlington,
Arlington, Texas 76019
loVely@uta.edu
Received September 2, 2008
ABSTRACT
The first total synthesis of the Leucetta alkaloid calcaridine A is described based on a biosynthetic postulate. Application of an oxidative
rearrangement of a 4,5-disubstituted imidazole leads to the formation of both calcaridine A and epi-calcaridine A. An X-ray crystal structure
determination on the latter has allowed the assignment of the relative configuration of the epimeric natural product and calcaridine A by
extrapolation.
2-Aminoimidazole-containing alkaloids isolated from marine
sponges have recently captured the attention of a number of
synthetic groups, in particular, several members of the oroidin
family.1-6 Other families of imidazole-containing alkaloids,
including examples isolated from Leucetta sponges, have
similarly attracted the attention of several groups.7-9 Re-
cently, Crews and co-workers reported a series of structurally
novel natural products 1-4 (Figure 1) isolated from a Fijian
marine sponge, Leucetta sp., some of which have modest
antibacterial activity.10,11 Some concerns have been raised
based on synthetic studies directed toward spiroleucettadine
(2) with respect to the accuracy of the assigned struc-
ture.12-14 This structural ambiguity notwithstanding, within
each of these compounds, a 2-aminoimidazole moiety and
two benzyl moieties can be identified, although there are
differences in the position of oxidation. There are obvious,
if experimentally undefined, biosynthetic relationships be-
tween these molecules, and thus an approach to one may
provide intermediates that can be used en route to other
family members. In both the Crews reports,11 and in a
subsequent report by Watson and co-workers of an approach
to the assigned structure of spiroleucettadine (2),12 it is
suggested that calcaridine A (1) and the other congeners 2-4
are derived from rearrangement and/or oxidation chemistry
of naamine A15-17 (14-desmethoxy 6) or a closely related
derivative.10-12 This particular postulate led us to speculate
that calcaridine A, at least, is formed by an oxidative
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(2) Weinreb, S. M. Nat. Prod. Rep. 2007, 24, 931
(3) He, Y.; Du, H.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965
(4) Jacquot, D. E. N.; Lindel, T. Curr. Org. Chem. 2005, 9, 1551
(5) Blunt, J. W.; Copp, B. R.; Hu, W.-P.; Munro, M. H. G.; Northcote,
P. T.; Prinsep, M. R. Nat. Prod. Rep. 2008, 25, 35
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(7) Zhong, J. Nat. Prod. Rep. 2005, 22, 196
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Yamashita, M.; Ohta, S. J. Chem. Soc., Perkin Trans. 1 2002, 1061
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Ohta, S. J. Chem. Soc., Perkin Trans. 1 2001, 3095
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(16) Carmely, S.; Ilan, M.; Kashman, Y. Tetrahedron 1989, 45, 2193
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10.1021/ol802018r CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

rearrangement of an intermediate that we term 14-methox-
ynaamine A (6). Although 6 appears to be unknown in the
literature at the present time, several years ago the N-
substituted derivative, 14-methoxynaamidine A (5) was
isolated from a Leucetta sp. sponge, and therefore, it is
tempting to speculate that 6 is a biosynthetic precursor to
both 1 and 5.18 In this communication, we describe the
successful execution of a “biomimetically inspired” approach
to (()-calcaridine A (1) which employs our recently
discovered oxidative rearrangement of 4,5-disubstituted
imidazoles to the corresponding 4,4-disubstituted-5-imida-
zolone.19-21 Although calcaridine A may not be considered
a complex and challenging natural product per se, it contains
two vicinal stereocenters for which neither the absolute nor
the relative stereochemistry was reported (our synthetic
studies have led to the assignment of the relative stereo-
chemistry). In addition, in the isolation reports, no description
of the biological activity of this natural product was provided,
and these endeavors should provide sufficient material to
facilitate such an investigation.
imidazole ring.3 Toward this end, we have found that 4,5-
disubstituted imidazoles on reaction with dimethyldioxirane
or N-sulfonyloxaziridines undergo a rapid rearrangement to
5-imidazolones or, in some cases, oxidative additions.19,21,22
On the basis of these discoveries, we believed that these
reactions might prove useful en route to the Leucetta
alkaloids 1-4 depicted in Figure 1.10,11 However, prior to
the work described herein, all of the reported examples are
based on oxidation of tetrahydrobenzimidazole derivatives;
therefore, if the rearrangement reaction were to be employed
in the present setting, this would suggest 6 as a precursor,
constituting a new class of substrates for this chemistry
(Figure 2). This rearrangement substrate would then be
Figure 2. Retrosynthetic analysis of calcaridine A.
accessible from the corresponding 4,5-diiodoimidazole via
a sequence of position selective metalation reactions, which
based on our own work22-24 and others25-29 it is known
that this can be executed in the order 5-, 4-, and then
2-positions.
Our initial studies centered on the alkylation of diiodoimi-
dazole 8 at the 5-position; this was attempted first by metalation
(I f MgBr), transmetalation (MgBr f CuX), and then
treatment with the appropriate benzyl bromide derivative.26
Unfortunately, the desired product was not obtained in this case,
but rather the imidazolium salt was isolated. It was subsequently
determined that the required adduct could be prepared by
reaction of the in situ generated 5-imidazolyl Grignard with
Bn-protected benzaldehyde derivative 9 and ionic reduction of
the hydroxyl moiety in 10 which provided 7 (Scheme 1).8 Initial
attempts to install the second benzylic substituent via similar
metalation chemistry and reaction with anisaldehyde were
Figure 1. Selected Leucetta alkaloids.
We have for some time had an interest in the development
of new methods and strategies for the construction of
complex imidazole-containing natural products from simple
imidazole derivatives, rather than de novo synthesis of the
(22) Lovely, C. J.; Du, H.; Sivappa, R.; Bhandari, M. K.; He, Y.; Dias,
H. V. R. J. Org. Chem. 2007, 72, 3741
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(23) Chen, Y.; Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett. 2003,
44, 1379
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(24) Chen, Y.; Ekanayake, V.; Lovely, C. J. Heterocycles 2007, 74, 873
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(18) Mancini, I.; Guella, G.; Debitus, C.; Pietra, F. HelV. Chim. Acta
1995, 78, 1178.
(25) Carver, D. S.; Lindell, S. D.; Saville-Stones, E. A. Tetrahedron
1997, 53, 14481
(26) Yang, X.; Knochel, P. Chem. Commun. 2006, 2170
(27) Abarbri, M.; Thibonnet, J.; Be´rillon, L.; Dehmel, F.; Rottla¨nder,
M.; Knochel, P. J. Org. Chem. 2000, 65, 4618
(28) Dehmel, F.; Abarbri, M.; Knochel, P. Synlett 2000, 345
(29) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F.; Kopp, F.;
Korn, T.; Sapountzis, I.; Vu, V. Angew. Chem., Int. Ed. 2003, 42, 4302.
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(19) Sivappa, R.; Koswatta, P.; Lovely, C. J. Tetrahedron Lett. 2007,
.
48, 5771
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(20) Sivappa, R.; Hernandez, N. M.; He, Y.; Lovely, C. J. Org. Lett.
2007, 9, 3861
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(21) Lovely, C. J.; Du, H.; He, Y.; Dias, H. V. R. Org. Lett. 2004, 6,
735
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5056
Org. Lett., Vol. 10, No. 21, 2008

rearrangement substrate 6 in good yield. We were delighted
to discover that this substrate underwent oxidative rearrange-
ment upon treatment with an N-sulfonyloxaziridine 15 in
MeOH at 40 °C.19,31 The reaction proceeded in a modest
54% yield (unoptimized), but unfortunately produced the
rearrangement products 1 and epi-1 as 2:1 mixture of
diastereomers based on 1H NMR spectroscopy, favoring the
epimeric natural product. This problem was exacerbated by
virtue of the difficulty encountered during attempted chro-
matographic separation of the two diastereomers.32
Scheme 1
As a result of the poor diastereoselectivity (and the
subsequent purification issues), we decided to modify our
approach by interchanging the locus of the two benzylic
fragments with the idea that the presence of the chiral center
closer to the 5-position, where the oxygen transfer occurs,
should lead to improved diastereoselectivity. The construction
of the requisite substrate again began from 8 by metalation
and reaction with N-methylformanilide (Scheme 3), providing
unsuccessful. However, metalation and reaction with N-meth-
ylformanilide gave the corresponding aldehyde 11 in good yield,
which on reaction the Grignard reagent derived from bromoani-
sole provided the desired alcohol 12. Methylation of 12 was
readily accomplished on exposure of 11 to methanol in the
presence of trifluoroacetic acid.
Scheme 3
Introduction of the 2-amino group was carried out by C2-
lithiation (n-BuLi) and reaction with TsN3 (Scheme 2).30
Scheme 2
the aldehyde 16 in good yield. The aldehyde was converted
to the ethylene ketal 17, and then metalation and treatment
with the benzyl-protected benzaldehyde derivative 9 provided
18. Alcohol 18 was deprotected with aqueous HCl and
subjected to an ionic reduction of the doubly benzylic alcohol
with Et3SiH/TFA providing aldehyde 19. A subsequent
Grignard reaction with p-anisylmagnesium bromide gave
Simultaneous reduction of the azide and debenzylation was
accomplished with Pd(OH)2-C/H2, providing the requisite
(31) Attempts to conduct the rearrangement with DMDO were unsuc-
cessful, leading to the formation of complex reaction mixtures
.
(32) It was subsequently determined that the diastereomers could be
separated by fractional recrystallization by seeding the mixture with the
non-naturally occurring diastereomer.
(30) Kawasaki, I.; Taguchi, Y.; Yamashita, M.; Ohta, S. Heterocycles
1996, 43, 1375.
Org. Lett., Vol. 10, No. 21, 2008
5057

alcohol 20, which was then converted to the methyl ether
21 (NaH, MeI). Introduction of the azide via metalation at
C2 and trapping with TsN3 afforded 22 (Scheme 3).
Exposure of 22 to Pd(OH)2-C/H2 led to reduction of both
the azide and the hydrogenolysis of the O-benzyl moiety,
providing the key rearrangement substrate 23 (Scheme 4).
which involved catalytic hydrogenation, one of which led
cleanly to calcaridine A (1), and the other to epi-calcaridine
A epi-1. Synthetic and natural calcaridine A exhibited
identical NMR data; however, our synthetic material was
isolated as a solid, whereas the natural material was isolated
as an oil; presumably this reflects differences of scale, purity,
or perhaps the fact that the synthetic material is racemic.
During the characterization process, it was noted that epi-
calcaridine A epi-1 formed nice crystals from MeOH-D4,
one of which was subjected to X-ray crystallography, which
indicated a syn arrangement of the imidazolone nitrogen and
the methoxy moiety.33 The structure clearly confirms that
the rearranged product has the correct connectivity expected
from this sequence and provides the relative configuration
of the two chiral centers. This in turn allowed the assignment
of the relative configuration of calcaridine A (1) as indicated
in Scheme 4.
Scheme 4
The present report constitutes the first description of a total
synthesis of the Leucetta alkaloid calcaridine A, which
employs an oxidative rearrangement of a polysubstituted
imidazole. These are the first examples of rearrangements
involving substrates other than a tetrahydrobenzimidazole-
type derivative. While these experiments do not prove that
calcaridine A is formed biosynthetically via an oxidative
rearrangement of 14-methoxynaamine A, they do demon-
strate that it is a feasible pathway. Although chemically the
rearrangement exhibits poor diastereoselectivity, an enzyme-
mediated process might be expected to proceed with
substantially higher levels of selectivity. In addition to the
total synthesis, we have determined the relative stereochem-
istry of the natural product through X-ray crystallography
of the epimeric congener. Present efforts are directed toward
improving the diastereoselectivity, developing an asymmetric
synthesis, and investigating the biological activity of this
natural product and its epimer.
Treatment of 23 with the N-sulfonyloxaziridine 15 also led
to an oxidative rearrangement, providing a 1:1 mixture of
calcaridine A (1) and epi-calcaridine A epi-1. Although there
was a small change in the diastereoselectivity in favor of
the natural product, it was certainly not to the extent that
we had hoped and expected. At this point, we decided to
investigate whether rearrangement of a precursor, in par-
ticular 22, might led to improved selectivities and facilitate
separation of the epimeric imidazolones. We were delighted
to discover that azide 22 underwent rearrangement on
treatment with 15 to provide a 1:1 mixture of chromato-
graphically separable imidazolones 24 and epi-24. At this
point, we did not know for certain which of the two azides
possessed the appropriate relative stereochemistry for con-
version to calcaridine A, although one had a strikingly similar
NMR spectrum to 1. Therefore, each of these rearrangement
products was taken on individually through the next step
Acknowledgment. This work was supported by the Robert
A. Welch Foundation (Y-1362) and the NIH (GM065503).
The NSF (CHE-9601771 and CHE-0234811) is thanked for
partial funding of the purchase of the NMR spectrometers
used in this study.
Supporting Information Available: Detailed experimen-
1
tal procedures and copies of H and 13C NMR spectra for
all new compounds. The X-ray structure of epi-1 and
associated CIF. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL802018R
(33) For details of this determination, see Supplementary Information.
5058
Org. Lett., Vol. 10, No. 21, 2008