Studies toward the total synthesis of axinellamine and massadine

Article abstract of DOI:10.1021/ol0711568

Intramolecular Diels-Alder reactions of several N-O linked 4-vinylimidazole dimers provide the expected adduct in moderate to good yield as a single, all trans stereoisomer, along with smaller amounts of the inverse electron demand adduct. Oxidative rearr

Full text of DOI:10.1021/ol0711568

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3861-3864
Studies toward the Total Synthesis of
Axinellamine and Massadine
Rasapalli Sivappa, Nora M. Hernandez, Yong He, and Carl J. Lovely*
Department of Chemistry and Biochemistry, The UniVersity of Texas at Arlington,
Arlington, Texas 76019
loVely@uta.edu
Received May 17, 2007
ABSTRACT
Intramolecular Diels−Alder reactions of several N−O linked 4-vinylimidazole dimers provide the expected adduct in moderate to good yield as
a single, all trans stereoisomer, along with smaller amounts of the inverse electron demand adduct. Oxidative rearrangement of the cycloadducts
occurs on treatment with Davis’ reagent, providing a single spiro imidazolone in good yield and with excellent levels of stereocontrol albeit
epimeric at the spiro center found in axinellamine and massadine.
The dimeric pyrrole-imidazole alkaloids axinellamine A (1)1,2
and massadine (2)3 were recently isolated from the marine
sponges Axinella sp. and Stylissa aff. massa, respectively
(Figure 1). These marine natural products are members of
the oroidin family of sponge metabolites and are formally
derived from the dimerization of two molecules of oroidin.4
In addition to their complex structures, both 1 and 2 display
substantial biological activity as an antibacterial agent
(against Helicobacter pylori) and as a geranylgeranyltrans-
ferase inhibitor, respectively. Although these molecules ex-
hibit different constitutions, one key disconnection (1 f 3;
2 f 3, Figure 1) reveals that they are in fact very closely
related. The differences of consequence relate to the con-
nectivity of the two imidazole moieties (C-N vs C-O) and
the nature of the C13 or C14 substituent (Cl vs OH). In other
words, strategically, they might be accessible from a com-
mon, and possibly late stage, intermediate 3. It is also of
note that these two alkaloids bear some resemblance to
palau’amine, at least around the polysubstituted cyclopentane
moiety.5,6
Over the past few years, our group has developed an
interest in the elaboration of simple imidazoles into more
complex derivatives, with the long-term goal of utilizing this
chemistry in natural product total synthesis.7 Among the key
transformations that we have developed are the Diels-Alder
(5) (a) Kinnel, R. B.; Gehrken, H. P.; Scheuer, P. J. J. Am. Chem. Soc.
1993, 115, 3376. (b) Kinnel, R.; Gehrken, H.-P.; Swali, R.; Skoropowski,
G.; Scheuer, P. J. J. Org. Chem. 1998, 63, 3281. For synthetic studies, see:
(c) Jacquot, D. E. N.; Lindel, T. Curr. Org. Chem. 2005, 9, 1551 and
ref 4.
(6) Very recently, the stereochemical assignment of palau’amine has been
called into question, with three almost simultaneous reports suggesting that
palau’amine does in fact share a common stereochemistry with both the
axinellamine family and massadine. (a) Kobayashi, H.; Kitamura, K.; Nagai,
K.; Nakao, Y.; Fusetani, N.; van Soest, R. W. M.; Matsunaga, S.
Tetrahedron Lett. 2007, 48, 2127. (b) Grube, A.; Ko¨ck, M. Angew. Chem.,
Int. Ed. 2007, 46, 2320. (c) Buchanan, M. S.; Carroll, A. R.; Addepalli, R.;
Avery, V. M.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 2007, 72,
2309. Therefore, our approach to 1 and 2 may in fact be applicable to
palau’amine’s revised structure.
(1) Urban, S.; de Almeida Leone, P.; Carroll, A. R.; Fechner, G. A.;
Smith, J.; Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 1999, 64, 731.
(2) For synthetic efforts toward 1, see: (a) Starr, J. T.; Koch, G.; Carreira,
E. M. J. Am. Chem. Soc. 2000, 122, 8793. (b) Dilley, A. S.; Romo, D.
Org. Lett. 2001, 3, 1535. (c) Dransfield, P. J.; Wang, S.; Dilley, A.; Romo,
D. Org. Lett. 2005, 7, 1679. (d) Koenig, S. G.; Miller, S. M.; Leonard, K.
A.; Lowe, R. S.; Chen, B. C.; Austin, D. J. Org. Lett. 2003, 5, 2203. (e)
Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.; Doundou-
lakis, T.; Harran, P. G. Angew. Chem., Int. Ed. 2005, 44, 765. (f) Tan, X.;
Chen, C. Angew. Chem., Int. Ed. 2006, 45, 4345.
(3) Nishimura, S.; Matsunaga, S.; Shibazaki, M.; Suzuki, K.; Furihata,
K.; van Soest, R. W. M.; Fusetani, N. Org. Lett. 2003, 5, 2255.
(4) For a general review of synthetic studies toward the oroidin family
of alkaloids, see: Hoffmann, H.; Lindel, T. Synthesis 2003, 1753.
(7) Du, H.; He, Y.; Sivappa, R.; Lovely, C. J. Synlett 2006, 965.
10.1021/ol0711568 CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/06/2007

strategy to effect, in our approach to the oroidin dimer,
ageliferin.10,12,13 However, in this latter study, the dimethyl-
aminosulfonyl (Me2NSO2 ) DMAS) group was used to
protect the imidazole, and it has been found that the electron-
withdrawing nature of this substituent is not conducive to
our oxidative rearrangement chemistry.9 Therefore, the
preparation of more electron-rich derivatives was necessary.
Although we had wanted to investigate this chemistry for
some time, the preparation of the requisite substrates proved
to be rather problematic due to competitive allylic rearrange-
ment in simple nucleophilic substitution reactions until we
discovered that Pd-catalyzed π-allyl substitution reactions
provided an expedient solution to this problem.14,15 Applica-
tion of this chemistry allowed efficient access to several
homodimers16 (PG1 ) PG2 ) Bn or SEM, 10aa and 10bb)
and heterodimers (PG1 ) DMAS; PG2 ) Bn or SEM, 10ac
and 10bc, Scheme 1). The precursor hydroxamic acids 8a-c
Scheme 1. Construction of the Cycloaddition Precursors
Figure 1. Retrosynthetic analysis of axinellamine A and massadine.
(DA) reactions of vinylimidazoles8 and the oxidative rear-
rangement of tetrahydrobenzimidazoles.9 As a result of these
studies, we were able to propose an approach to 1 and 2
depicted retrosynthetically in Figure 1, which involves an
intramolecular DA reaction of a bisvinylimidazole 6 f 4
and its subsequent rearrangement and elaboration of the tether
4 f 3. In this communication, we describe the investigation
and execution of the initial phases of this strategy.
Earlier studies from our lab with amide-linked dimers
related to 6 indicated that these were viable substrates in
the intramolecular DA reaction,8d leading stereoselectively
to the required all-trans substituted cycloadducts, but these
were not ideal due to selectivity issues relating to normal vs
inverse electron demand cyclization pathways (cf. 11 and
12 in Scheme 2).3,10 This was further exacerbated by the
difficulty in elaborating the amide tether under sufficiently
mild conditions that did not lead to concomitant imidazole
nitrogen deprotection. To circumvent this deficiency, we
explored the use of hydroxamates which provide tethers that
can be cleaved relatively easily.2d,11 We have used this
can be easily obtained from the corresponding urocanic acid
derivatives 7a-c17 by ester hydrolysis, conversion to the acid
chloride, and coupling with benzhydryl hydroxylamine
(Scheme 1).18,19 The allylic carbonates 9a,b13 were prepared
by DIBAL reduction of the same esters 7a,b and then
converted to the corresponding carbonates. Reaction of 8a-c
and 9a,b in the presence of Pd2dba3 provided the required
dimers 10aa-bb, 10ac, and 10bc in generally good yield
(8) Intermolecular variants: (a) Lovely, C. J.; Du, H.; Dias, H. V. R.
Org. Lett. 2001, 3, 1319. (b) Lovely, C. J.; Du, H.; Dias, H. V. R.
Heterocycles 2003, 60, 1. (c) Du, H.; Sivappa, R.; Bhandari, M. K.; He,
Y.; Dias, H. V. R.; Lovely, C. J. J. Org. Chem. 2007, 72, 3741.
Intramolecular variants: (d) He, Y.; Chen, Y.; Wu, H.; Lovely, C. J. Org.
Lett. 2003, 5, 3623.
(9) Lovely, C. J.; Du, H.; He, Y.; Dias, H. V. R. Org. Lett. 2004, 6,
735.
(10) Simple unsaturated esters were poor substrates in the intramolecular
Diels-Alder reaction. He, Y. Ph.D. Dissertation, The University of Texas
at Arlington, 2005.
(12) For isolation see: (a) Kobayashi, J.; Tsuda, M.; Murayama, T.;
Nakamura, H.; Ohizumi, Y.; Ishibashi, M.; Iwamura, M.; Ohta, T.; Nozoe,
S. Tetrahedron 1990, 46, 5579. (b) Keifer, P. A.; Schwartz, R. E.; Koker,
M. E. S.; Hughes, R. G.; Rittschof, D.; Rinehart, K. L. J. Org. Chem. 1991,
56, 2965. (c) Williams, D. H.; Faulkner, D. J. Tetrahedron 1996, 52, 5381.
For total synthesis, see: (d) O’Malley, D. P.; Li, K.; Maue, M.; Zografos,
A.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 4762.
(11) Ishikawa, T.; Senzaki, M.; Kadoya, R.; Morimoto, T.; Miyake, N.;
Izawa, M.; Saito, S.; Kobayashi J. Am. Chem. Soc. 2001, 123, 4607. See
also ref 2d.
(13) Sivappa, R.; He, Y.; Krishnamoorthy, P.; Lovely, C. J. unpublished
results.
3862
Org. Lett., Vol. 9, No. 20, 2007

Scheme 2. Cycloaddition and Oxidative Rearrangement
(Scheme 1). Subjection of each dimer to DA reaction in
stants were consistent with those found in the analogous
DMAS-protected system for which an X-ray structure was
obtained.10 Interestingly, it was observed that the homodimers
10aa and 10bb afforded poorer chemoselectivity than the
heterodimers 10ac and 10bc in the cycloaddition chemistry.
This observation is consistent with other types of dimeric
imidazole systems that we have evaluated. In the case of
the heterodimers, the dienophilic component is more electron
deficient than the diene, and so presumably this leads to a
more pronounced HOMO-LUMO gap between the two
possible cycloaddition modes.
As indicated above in Figure 1, the next step in our
strategy required the oxidative rearrangement of the tetrahy-
drobenzimidazoles derived from the DA reaction. Recent
studies in our lab have demonstrated that Davis’ reagents
(N-sulfonyloxaziridines) are excellent reagents to effect this
transformation.22,23 We were delighted to discover that all
four major cycloadducts underwent smooth rearrangement
to a single spiro-fused 5-imidazolone in moderate to excellent
yield on treatment with 13 in CHCl3 at 45-50 °C (Scheme
2, Table 1). This transformation exhibited high levels of
chemoselectivity with only the imidazole within the tetrahy-
drobenzimidazole framework undergoing oxidation and high
levels of stereoselectivity, although at this point we were
unable to establish the stereochemistry of the spiro fusion
(vide infra).
toluene at 150 °C (sealed tube) led to a smooth cycloaddition
providing a mixture of the normal 11 and inverse electron
demand product 12, favoring the normal addition product
(7-3:1, Table 1). Under the reaction conditions employed,
Table 1. Cycloaddition (10 f 11 + 12) and Rearrangement
Yields (11 f 14)
yield/%
substrate
product
(N:I)a
product
yield/%
81
10aa
11aa/12aa
68/21
(3.9:1)
62/20
(3:1)
84/10
(7:1)
14aa
10bb
10ac
10bc
11bb/12bb
11ac/12ac
11bc/12bc
14bb
14ac
14bc
47
71
61
68/7
(6:1)
a
N:I ) normal:inverse electron demand Diels-Alder products. The
1
ratio was determined by integration values in the H NMR spectra of the
crude reaction mixtures.
the initial cycloadduct (cf. 5, Figure 1) was not obtained.20
The major cycloadduct could be separated in reasonable
efficiencies by chromatography, and analysis of the magni-
tudes of the coupling constants for the bridgehead proton
With the spiro-fused systems in hand, we investigated
elaboration of the hydroxamate tether in 14ac through
reductive cleavage with SmI2, which in addition to reducing
the N-O bond led to reduction of the CdN bond of the
imidazolone in moderate overall yield (15, Scheme 3).24 It
was found that this reaction was somewhat capricious
providing variable yields and product distributions. Therefore,
we subjected 14ac to reduction with NaBH4, which only
H
8a with H4a (J ∼ 10 Hz) and H9 (J ∼ 11-12 Hz) in the 1H
NMR spectra clearly indicated that these cycloadducts
possessed all trans stereochemistry.21 These coupling con-
(14) Krishnamoorthy, P.; Sivappa, R.; Du, H.; Lovely, C. J. Tetrahedron
2006, 62, 10555.
(15) (a) Miyabe, H.; Yoshida, K.; Matsumura, A.; Yamauchi, M.;
Takemoto, Y. Synlett 2003, 567. (b) Miyabe, H.; Matsumura, A.; Yoshida,
K.; Yamauchi, M.; Takemoto, Y. Synlett 2004, 2123. (c) Miyabe, H.;
Yoshida, K.; Reddy, V. K.; Matsumura, A.; Takemoto, Y. J. Org. Chem.
2005, 70, 5630.
(16) Although strictly these compounds are not homodimers, we use this
term to refer to compounds in which the two imidazole nitrogen-protecting
groups are identical. Where these groups are different, we refer to them as
heterodimers.
(19) Adam, W.; Beck, A. K.; Pichota, A.; Saha-Moller, C. R.; Seebach,
D.; Vogl, N.; Zhang, R. Tetrahedron: Asymmetry 2003, 14, 1355.
(20) We have found that when these reactions are carried out under
microwave irradiation and high dilutions the initial adduct can be obtained.
See ref 10.
(21) This was supported by X-ray analysis of a derivative from 11ac
(see Supporting Information).
(17) He, Y.; Chen, Y.; Du, H.; Schmid, L. A.; Lovely, C. J. Tetrahedron
Lett. 2004, 45, 5529.
(18) Early experiments with benzyl hydroxamates indicated that these
were poorer substrates in the Diels-Alder reaction, and so the bulkier and
ultimately superior benzhydryl group was employed. See ref 10.
(22) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
(23) Sivappa, R.; Koswatta, P.; Lovely, C. J. Tetrahedron Lett. 2007,
48, 5771.
(24) Similar results have been obtained with 14aa. Hernandez, N. M.,
unpublished results.
Org. Lett., Vol. 9, No. 20, 2007
3863

the DA reaction, of the hydroxymethyl, amide, and imidazole
substituents as required in 1 and 2. Unfortunately however,
the X-ray structure also revealed that the spiro center is
epimeric to that found in axinellamine and massadine.26 We
briefly examined other oxidants for initiating the rearrange-
ment but found that either they gave the same product
(DMDO, 56%)9 or no reaction occurred (MCPBA).2f As we
had found that the CdN of the imidazolone could be reduced
with NaBH4, this provided an opportunity to correlate the
stereochemistry of the rearrangement products obtained via
both routes. Accordingly, 17 was treated with NaBH4, and
this provided the same imidazolinone 15 as the first route
(11ac f 14ac f 15) and served to confirm the relative
stereochemistry of this rearrangement project. By extrapola-
tion, we have assigned the stereochemistry of the rearrange-
ment products (14aa, bb, bc) obtained from the major Diels-
Alder cycloadducts.
Scheme 3. Elaboration of the Cycloadduct
In summary, we have described a concise approach to a
tetrasubstituted spiro cyclopentyl imidazolone fragment
related to the one found in axinellamine A and massadine
through an intramolecular Diels-Alder/oxidative rearrange-
ment strategy. The hydroxamate substrates provide a con-
venient method for tethering the two imidazole fragments,
which can be cleaved readily by reduction with SmI2.
Although oxidative rearrangement leads to a single stereo-
isomer, the spiro ring fusion is epimeric to that found in
these natural products. Current efforts are focused on solving
this stereochemical flaw, on incorporation of the additional
heteroatom, and on end game strategies.
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. We would also like to
express our thanks to Prof. Rasika Dias (UT Arlington) for
obtaining and solving the X-ray structure reported in this
paper.
reduced the CdN moiety, followed by treatment with SmI2,
which provided 15 cleanly in moderate yield (Scheme 3).25
To obviate the two-step reduction sequence described
above, we also investigated elaboration of the cycloadducts
prior to oxidative rearrangement. It was found that the N-O
bond in 11ac can be cleaved using SmI2, providing the
corresponding hydroxyamide 16 in good yield. This substrate
also undergoes the oxidative rearrangement reaction with the
Davis reagent, affording the spiro-fused imidazolone as a
single diastereomer 17. After conversion of the hydroxyl
moiety into the p-nitrobenzoate, the resulting compound
provided crystals suitable for X-ray crystallography which
confirmed the all-trans relative stereochemistry, derived from
Supporting Information Available: Detailed experi-
1
mental procedures and copies of H and 13C NMR spectra
for all new compounds. The X-ray structure of 17-PNB ester
and associated CIF. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0711568
(25) We attempted to obtain a crystal structure of this compound (after
treatment with p-nitrobenzoyl chloride, which led to benzoylation at both
nitrogen and oxygen). This revealed that the molecule had the indicated
stereochemistry, but the quality of the data was poor.
(26) Baran and co-workers have made a similar stereochemical observa-
tion in their attempts to rearrange ageliferin (via dihydroxylation and base-
induced rearrangement) to the axinellamine skeleton. See ref 12d.
3864
Org. Lett., Vol. 9, No. 20, 2007