Total syntheses of kealiinines A-C

Article abstract of DOI:10.1021/ol302958e

Short total syntheses of the Leucetta-derived alkaloids, kealiinines A-C, have been accomplished using an intramolecular Friedel-Crafts-dehydration sequence of a bis benzylic diol. The precursor diol was obtained through a series of position-specific Grignard reactions from 1-methyl-4,5- diiodoimidazole. C2-Azidation and hydrogenation of the azide then provided the reported structures of kealiinines A-C. While the ¹H NMR data did not completely match for these materials, the HPLC data were consistent with the assigned structure of these alkaloids.

Full text of DOI:10.1021/ol302958e

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6210–6213
Total Syntheses of Kealiinines AꢀC
Jayanta Das, Panduka B. Koswatta, J. Daniel Jones, Muhammed Yousufuddin,† and
Carl J. Lovely*
Department of Chemistry and Biochemistry and Center for Nanostructured Materials,
The University of Texas at Arlington, Arlington, Texas 76019, United States
lovely@uta.edu
Received October 27, 2012
ABSTRACT
Short total syntheses of the Leucetta-derived alkaloids, kealiinines AꢀC, have been accomplished using an intramolecular FriedelꢀCraftsꢀ
dehydration sequence of a bis benzylic diol. The precursor diol was obtained through a series of position-specific Grignard reactions from
1-methyl-4,5-diiodoimidazole. C2-Azidation and hydrogenation of the azide then provided the reported structures of kealiinines AꢀC. While the
1H NMR data did not completely match for these materials, the HPLC data were consistent with the assigned structure of these alkaloids.
The Leucetta alkaloids are a group of approximately 60
2-aminoimidazole alkaloids1 isolated from sponges of the
Leucetta and Clathrinafamilies.2ꢀ4 Structurally, all of these
alkaloids contain at least one oxygenated benzyl group
(Figures1 and2), e.g., clathridineA (1),5 andin manycases,
there are two benzyl groups, e.g., naamidine G (2).6 Within
this collection of alkaloids a subgroup 6ꢀ8 containing a
naphthimidazole moiety has been reported that still retains
the two benzylic groups,7ꢀ9 but these are now embedded
within the heterocyclic framework (Figure 2). Kealiinines
AꢀC (8aꢀc)7 were isolated by the Proksch group in 2004,
along with naamine G and naamidine H (3); the former
are structurally related to the more highly oxygenated
kealiiquinone (6)9 and 2-deoxy-2-aminokealiiquinone (7).8
† Center for Nanostructured Materials.
(1) Jin, Z. J. Nat. Prod. 2011, 28, 1143.
(2) Koswatta, P. B.; Lovely, C. J. Nat. Prod. Rep. 2011, 28, 511.
(3) Sullivan, J. D.; Giles, R. L.; Looper, R. E. Curr. Bioact. Compd.
2009, 5, 39.
Figure 1. Structures of the Leucetta family of alkaloids.
(4) Roue, M.; Quevrain, E.; Domart-Coulon, I.; Bourguet-Kondracki,
M. L. Nat. Prod. Rep. 2012, 29, 739.
(5) Ciminiello, P.; Fattorusso, E.; Magno, S.; Mangoni, A. Tetrahedron
1989, 45, 3873.
(6) Mancini, I.; Guella, G.; Debitus, C.; Pietra, F. Helv. Chim. Acta
It has been suggested that kealiinine C (8c) may serve as a
biosynthetic precursor to 6 and 7,7 but there is no experi-
mental evidence to support this hypothesis.10 No bioactivity
1995, 78, 1178.
(7) Hassan, W.; Edrada, R.; Ebel, R.; Wray, V.; Berg, A.; Van Soest,
was reported by Proksch for 8b and 8c,7 presumably
R.; Wiryowidagdo, S.; Proksch, P. J. Nat. Prod. 2004, 67, 817.
(8) Fu, X.; Barnes, J. R.; Do, T.; Schmitz, F. J. J. Nat. Prod. 1997, 60,
497.
(9) Akee, R. K.; Carroll, T. R.; Yoshida, W. Y.; Scheuer, P. J.; Stout,
T. J.; Clardy, J. J. Org. Chem. 1990, 55, 1944.
(10) We have demonstrated the feasibility of such a transformation in
the conversion of a kealiinine-type intermediate into kealiiquinone and
2-deoxy-2-aminokealiiquinone.
r
10.1021/ol302958e
Published on Web 12/05/2012
2012 American Chemical Society

Figure 2. Putative biosynthetic relationships among the Leucetta alkaloids.
as a consequence of the modest amounts of material
isolated, but kealiinine A (8a) was shown to be active in
the brine shrimp toxicity assay.7 To date, only two pub-
lished synthetic studies toward this subgroup of alkaloids
have appeared resulting in a total synthesis of kealiiquinone
(6)11 and the non-natural 70-desmethyl derivative (4).12 Fur-
thermore, since the biological activity of the kealiinines
has not been extensively investigated, it would appear that
a program directed toward their synthesis is warranted.13
Over the past few years, our laboratory has developed
several synthetic methods for the total synthesis of
2-aminoimidazole alkaloids using site-selective functiona-
lization of polyhaloimidazoles. Using this strategy, we
have reported total syntheses of several Leucetta alkal-
oids including clathridine A (1),14 naamidine G (2),15
naamidine H (3),16 and calcaridine A (5).17 We have more
recently turned our attention to members of this class
containing a naphthimidazole framework such as kealii-
nines AꢀC (8aꢀc), kealiiquinone (6),12 and the 2-amino
congener 7. While the details of the biosynthesis of these
natural products remain to be elucidated experimentally,
hypothetical biosynthetic relationships between both the
simple systems and the more highly oxidized derivatives
are evident. It is thought that naamine-type systems 9 may
serve as precursors for other family members through net
oxidative functionalization (Figure 2). Some of these
potential relationships are outlined in Figure 2, and while
they are purely hypothetical, they have provided a frame-
work for our synthetic programs. Indeed, we have used
such a biomimetic strategy en route to calcaridine A (5) via
9 (R = X = Y = H, Z = OMe).17 It has been speculated
that the naphthimidazole framework arises from a net
oxidative coupling between C12 and C13 (kealiinine
numbering) and further oxidation to lead to the natural
product. Circumstantial evidence to support this idea
can be found in reports of C12-oxygenated naamidine
derivatives,6 but there is no experimental data to confirm
this hypothesis. From a synthetic perspective, one can
envision that a similar outcome might be obtained through
a FriedelꢀCrafts type of strategy to form the C12ꢀC13
bond followed by dehydration.11 Such a strategy in prin-
ciple would provide access to all family members with only
C2-amination and deprotection necessary. Oxidation of
the C-ring would provide an entry to kealiiquinone and
congeners.
(11) Kawasaki, I.; Taguchi, N.; Yamamoto, T.; Yamashita, M.;
Ohta, S. Tetrahedron Lett. 1995, 36, 8251.
(12) Lima, H. M.; Sivappa, R.; Yousufuddin, M.; Lovely, C. J. Org.
In order to establish the viability of the strategy we
selected kealiinine C (8c) as our first target, thereby avoid-
ing potential regioselectivity issues in the cyclization step
forming the naphthimidazole system (Scheme 1). In a
forward sense, metalation of 12 with EtMgBr in CH2Cl2
provides the 5-imidazolyl Grignard, which upon reac-
tion with the trimethoxybenzaldehyde 13c results in the
Lett. 2012, 14, 2274.
(13) While our manuscript was in preparation the total synthesis of
kealiinines A and B was reported; see: Gibbons, J. B.; Gligorich, K. M.;
Welm, B. E.; Looper, R. E. Org. Lett. 2012, 14, 4734.
(14) Koswatta, P. B.; Lovely, C. J. Tetrahedron Lett. 2009, 50, 4998.
(15) Koswatta, P. B.; Lovely, C. J. Tetrahedron Lett. 2010, 51, 164.
(16) Koswatta, P. B.; Lovely, C. J. Chem. Commun. 2010, 46, 2148.
(17) Koswatta, P. B.; Sivappa, R.; Dias, H. V. R.; Lovely, C. J. Org.
Lett. 2008, 10, 5055 and references cited therein.
Org. Lett., Vol. 14, No. 24, 2012
6211

Scheme 1. Assembly of the Benzimidazole Framework (for Yields, See Table 1)
formation of the corresponding alcohol 14c. Treatment of
alcohol 14c with excess EtMgBr leads to the formation of
Table 1. Yields for Synthesis of the Kealiinines AꢀC (8aꢀc)
the 4-imidazolyl Grignard, which reacts with N-methyl
formanilide (15), producing aldehyde 16c. Treatment of
aldehyde 16c with excess p-methoxyphenylmagnesium
bromide affords the diol 17c as an inconsequential diaste-
reomeric mixture in good yield. Attempts to introduce the
benzyl moiety directly, i.e., 14cf17c via metalation and
reaction with p-anisaldehyde, were not successful leading
to the two-step sequence described. Gratifyingly, treat-
ment of unpurified 17c with HCl resulted in an intramo-
lecular FriedelꢀCrafts cyclizationꢀdehydration sequence
to provide the naphthimidazole 18c, a result that was
confirmed by X-ray crystallography. C2-Metalation with
n-BuLi, followed by exposure to TrisN3, produced the
2-azido compound 19c. Subsequent treatment with Pdꢀ
C/H2 led to the reduction of the azide to the amine and the
completion of the synthesis of the kealiinine C (8c).
The 1H NMR spectroscopic data of synthetic kealiinine
C in DMSO-d6 were not in agreement with the data
reported for the natural product, and 13C NMR data were
not obtained for the natural product.7 For example, the
aromatic proton at C6 on the naphthimidazole framework
appeared at δ 7.33 in the synthetic material compared to δ
7.66 in the natural material. Similarly, there were some
inconsistencies with the signals due to the methyl sub-
stituents. In particular we noted methyl signals at 3.49
(N-Me) and 3.06 ppm (MeO at C11) in the synthetic
material, whereas in the naturally occurring material the
highest field signal was at 3.40 ppm. We had prepared
substantially more material than was isolated from the
sponge, and thus we hypothesized that the differences
simply may be due to concentration effects. However,
while dilution of NMR samples of synthetic material
resulted in some minor shift changes (Δδ ∼ 0.05 ppm),
the spectroscopic data were still not in agreement with that
reportedfor the natural product. Attemps toreproducethe
compd
14 (%)
16(%)
18(%)
19(%)
8(%)
a
b
c
70
72
87
70
70
70
65
70
65
69
69a
87
85a
a Confirmed by X-ray analysis.
“as isolated” sample by the addition of water and/or TFA
also failed to cause substantial changes in the chemical
shifts. While the connectivity of the naphthimidazole
framework and the relative location of the p-methoxyphe-
nyl and methyl groups was confirmed through the X-ray
analysis of 18c, it is conceivable that metalation with
n-BuLi may have occurred at sites other than the imidazole
C2. Fortunately, we were able to obtain an X-ray crystal
structure of our synthetic final product 8c, which unequi-
vocally indicated that the required substitution pattern
corresponding to the reported structure was obtained.
Interestingly, the X-ray structure revealed that we had
obtained the amino tautomer, rather than the imino
tautomer described for the natural product. While extra-
polating from the solid state to the solution phase must be
done with caution, one possible explanation for the dis-
crepancy in the spectroscopic data between the isolated
natural product and the synthetic material may lie in the
extent of the equilibrium. Since only a very small amount
of the natural material was isolated, the presence of
impurities in the natural sample may substantially influ-
ence the position of the tautomeric equilibrium, which
in turn may affect the chemical shifts of this material.
A related issue with tautomers has been observed with
kealiiquinone which was isolated as this enol tautomer,9
but the synthetic material was prepared as the keto form.11
6212
Org. Lett., Vol. 14, No. 24, 2012

product. Puzzlingly, however, the spectroscopic data for
both synthetic materials also did not coincide with the
data reported for by the Proksch laboratory. On the other
hand the chromatographic properties of the synthetic
and natural materials were identical based on HPLC data.
In the case of kealiinine A (8a), the 13C NMR data were
reported, but our data did not appear to match well either.
However, the major disagreements are largely confined to
carbons assigned to C4 and C5, which are consistent with
the hypothesis of the different tautomeric identities of the
isolated and synthetic materials.
Scheme 2. Completion of Kealiinine A (8a)
In summary, we have developed high-yielding, protecting-
group-free synthesis of the Leucetta alkaloids kealiinine
AꢀC (8aꢀc) using sequential and chemoselective halogenꢀ
magnesium exchange reactions. Subsequent FriedelꢀCrafts
cyclization and lithiation at C2 with electrophilic trapping
leads to introduction of the 2-amino moiety. While the
structures of the synthetic materials are secure and their
chromatographic properties match the natural materials,
the spectroscopic data do not match. One explanation for
these observations may be related to the preparation of the
amino form rather than the isolated imino forms. Attempts
to reproduce the spectroscopic characteristics of the as
isolated material through changing the sample concentra-
tion and introduction of additives have been unsuccessful.
To partially address this issue, the Proksch lab was kind
enough to perform comparative HPLC analysis of our
synthetic material with a natural product sample. This
analysis showed that the two samples coeluted, suggesting
that they were in fact chromatographically identical.18
Given that there was some uncertainty in the structure
of kealiinine C (8c), we decided to prepare the other
two family members, kealiinine A (8a) and B (8b). Their
syntheses follow largely the same strategy, simply substi-
tuting the appropriate benzaldehyde for 8a and 8b provid-
ing the targets in seven steps (11% overall yield) and six
steps (21% overall yield), respectively, from 12. In the case
of kealiinine A (8a), deprotection of the O-benzyl group
was accomplished prior to C2-azidation and reduction as
metalation was more effective with a free phenolic OH
(Scheme 2). X-ray crystallographic analysis of 20 unequi-
vocally confirmed the connectivity of the FriedelꢀCrafts
Acknowledgment. We would like to thank Prof. Peter
€
€
Proksch (Universitat Dusseldorf) for providing copies of
the original spectra of natural kealiinine C, for performing
the comparative HPLC analyses, and for valuable discus-
sion pertaining to the discrepancies in the data. We would
also like to thank Prof. Ryan Looper (University of Utah)
for valuable discussions and exchange of data prior to
publication. This work was supported by the Robert A.
Welch Foundation (Y-1362) and in part by the NIH
(GM065503). The NSF (CHE-0234811 and CHE-0840509)
is thanked for partial funding of the purchases of the NMR
spectrometers used in this work.
(18) An alternative interpretation of these observations is that the
assigned structure is in fact incorrect. To address this possibility, we
prepared an isomeric congener through similar chemistry and found that
although the NMR data were a better match (but not exact), the
chromatographic properties were substantially different from the natu-
rally occurring material.
Supporting Information Available. Detailed experimen-
1
tal procedures and copies of H and 13C NMR spectra
for all new compounds. Tabulated listing of NMR assign-
ments, copies of HSQC, HMBC and ROESY plots, and
comparative HPLC traces. CIFs for compounds 8c, 18c,
and 20. This information is free of charge from the
Internet at http://pubs.acs.org.This material is available
free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
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