Studies toward the total synthesis of the oroidin dimers

Article abstract of DOI:10.1039/b909482b

A Diels-Alder/rearrangement sequence is described for the construction of the core ring systems of several oroidin dimers, including ageliferin and palau'amine. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b909482b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Studies toward the total synthesis of the oroidin dimers†
Rasapalli Sivappa,‡ Sabuj Mukherjee, H. V. Rasika Dias* and Carl J. Lovely*
Received 14th May 2009, Accepted 23rd June 2009
First published as an Advance Article on the web 2nd July 2009
DOI: 10.1039/b909482b
A Diels–Alder/rearrangement sequence is described for the
construction of the core ring systems of several oroidin
dimers, including ageliferin and palau’amine.
involved a Diels–Alder (DA)-rearrangement sequence.5 We6 and
the Romo7 group have reported the successful execution of this
strategy in which an intermolecular DA reaction plays a prominent
role employing imidazoles and imidazolones respectively; in our
version leading to the construction of 4 (Fig. 1) containing the
DEF-ring substructure of the originally assigned structure of
palau’amine (3).8,9 Baran has also reported a ring contraction
strategy for the construction of the spiro fused bicycle system
foundinthe related familymembers axinellamine andmassadine.10
In this report, we disclose the evolution of our strategy in
which the key steps are an intramolecular DA reaction of a bis
imidazole-containing substrate,11 and its subsequent stereo- and
chemoselective oxidative rearrangement to provide the all trans-
substituted cyclopentane ring common to several members of the
oroidin family of alkaloids. This change in strategy permits the
incorporation of the whole contiguous carbon skeleton at an early
stage.
Palau’amine (1, Fig. 1), a hexacyclic bisguanidine-containing
alkaloid isolated from the marine sponge Styllotella aurantium
found off the Western Caroline Islands, is a member of the
oroidin family of alkaloids.1,2 This molecule has engendered
significant attention from the synthetic community, in large part,
as a consequence of the intricate and complex structure, and its
potent immunosuppressive activity. Of the six rings in this natural
product, only one is carbocyclic (E-ring), and it contains five of
the eight contiguous chiral centers present in this molecule, all
of which originally were reported to possess a syn relationship
(3, Fig. 1). However, recently, the original structure reported
by Scheuer and Kinnel has been revised to an all-trans relative
stereochemistry (1, Fig. 1), which is now consistent with several
other related oroidin dimers, suggesting that they have a common
biogenesis.3,4 As is often the case with structurally unusual natural
products, several imaginative approaches towards this alkaloid
have been reported, although no total synthesis has appeared
yet. Our own approach was guided by a biosynthetic proposal
that was suggested in the Scheuer and Kinnel report1 which
Our first generation plan focused on the construction of the
ABC rings of palau’amine through elaboration of the succinimide-
containing substrates related to 4 (Fig. 1), which were to be
assembled via an intermolecular DA reaction between a vinylim-
idazole and subsequent oxidative rearrangement.6,12 However,
several aspects of this approach became less attractive in light
of developments in a parallel investigation in our lab on the
intramolecular DA reaction. It was found in the course of
these studies that fairly elaborate systems, e.g., 5 (Scheme 1)
could be assembled extremely rapidly and these substrates would
Fig. 1 Palau’amine and related molecules.
Department of Chemistry and Biochemistry, The University of Texas at
Arlington, Arlington, USA. E-mail: lovely@uta.edu; Fax: +1 817-272-3808;
Tel: +1 817-272-5446. E-mail: dias@uta.edu; Fax: +1 817 272-3808; Tel: +1
817-272-2813
† Electronic supplementary information (ESI) available: Experimental and
characterization data for all new compounds. CCDC reference numbers
732270 (22a) and 734669 (22b). For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/b909482b
‡ Present address: Department of Chemistry and Biochemistry, University
of Massachusetts Dartmouth, North Dartmouth, MA 02747–2300, USA.
Scheme 1
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engage in cycloadditions with reasonable efficiencies. Most notable
were systems that potentially allowed access into the ageliferin13
and axinellamine7,14 families through the cyclization of pseudo
dimeric substrates such as 5 which afford the all trans substi-
tuted tetrahydrobenzimidazoles 6 on IMDA reaction (Scheme 1).
Subsequent reductive cleavage of the hydroxamate and oxidative
rearrangement with an N-sulfonyloxaziridine 8 provided the spiro
fused imidazolone 9. Unfortunately, the rearranged product was
epimeric at the spiro fused center preventing the further use of this
particular intermediate en route to axinellamine A or palau’amine
(1). However, if the stereochemical issue could be corrected, a
concise approach for the construction of the key EF-ring system
of palau’amine would be possible.
At the time that these studies were initiated they were directed
toward the original structure of palau’amine, i.e., 3 (Fig. 2). As
indicated above, the use of bis imidazole substrates potentially
increase convergency, and would provide substrates that could
utilize chemistries related to those used for the construction of
the monomeric oroidin alkaloid phakellin for the formation of
the BD-rings (10→3, Fig. 2).15 Thus, if an all cis analog of
9, i.e., 10 could be constructed, access to a palau’amine-like
precursor could be envisioned. However, rather than use a cis
substituted dienophile in our bis-imidazole approach delineated
in Scheme 1, we chose to employ a propiolic acid derivative
in the cycloaddition and perform a diastereocontrolled hydro-
genation on the resulting cycloalkene to establish the relative
stereochemistry (13→12→11).16 At the outset, this strategy had
several advantages over the chemistry depicted in Scheme 1; first
it would preclude the normal/inverse-electron demand selectivity
issue that complicates the dimer cycloadditions with amide and
hydroxamate derivatives. Second, it obviates concerns associated
with base-induced isomerization of the cis-double bond prior
to cycloaddition or epimerization at the carbon adjacent to the
carbonyl in the cycloadduct under the thermal reaction conditions.
We also had encouraging preliminary success17 with propiolate
derivatives in the IMDA reaction providing the more readily
elaborated lactone moiety to undertake the bis imidazole enyne
IMDA approach.
The first target in evaluating this strategy became the construc-
tion of the corresponding imidazolyl propiolic acid derivatives
17a–b, of which there were no previous reports. There are a
several examples of Sonogashira reactions involving haloimi-
dazole derivatives in the literature with propargyl alcohol or
amine derivatives, and so initially this pathway was followed.18
Although the cross-coupling reaction with protected propargyl
alcohol derivatives works very well, the approach was thwarted
by our inability to transform the alcohol to the corresponding
acid derivative. Attempts to employ methyl propiolate directly
in a Sonogashira cross coupling were partially successful on a
small scale, but unfortunately this route was compromised by poor
scalability (< 1 g).19 However, the use of the ortho ester derivative
15 provided a successful synthesis of the ethyl ester 16a–b after
in situ hydrolysis of the cross-coupled product.20 Subsequent
ester hydrolysis with LiOH provided the acid 17a–b, which upon
activation with DCC in the presence of camphorsulfonic acid and
DMAP,21 and coupling with the known allylic alcohol 188 provided
the key cyclization precursors 19a–b in good yield (Scheme 2).
Scheme 2
Heating a deoxygenated dichloromethane solution of the
enynes 19a–b at 130 ◦C in a sealed tube for 16 h led to
smooth cycloaddition and provision of the expected cycloadducts
20a–b in good yield (Scheme 3).◦Subsequent controlled catalytic
hydrogenation at 60 psi and 40 C over 10% Pd-C provided the
all-cis lactones 21a–b. Notably, this reaction was not accompanied
by significant reductive debenzylation, and the corresponding
tetrahydrobenzimidazoles 21a–b were obtained in 70–75% yield.
The initial assignment of the relative stereochemistry of the
reduction product was obtained by examination of the relevant
coupling constants of the bridgehead and benzylic protons. It has
been determined that J4a,7a = 8.7 Hz and J7a,8 = 8.7 Hz, which
are completely consistent with the indicated stereochemistry. We
Fig. 2
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more substituted (and presumably more electron rich) imidazole
in this reaction is noteworthy. We were also fortunate that both
22a and b were well-behaved crystalline solids, which gave crystals
suitable for X-ray crystallography (see Supporting Information
for details).¶ This not only confirms the stereochemical sense
of the spiro fusion, but also that the catalytic hydrogenation
leads to an all-cis fusion. Of particular note is the stereochemical
outcome of this rearrangement. Our previously reported studies
with all trans substituted systems14 and also one related substrate
reported by Baran and coworkers10 gives rise to an imidazolone
with the opposite stereochemistry, and this seemingly subtle
change in the relative stereochemistry of the substrate leads to a
complete changeover in selectivity. After some experimentation it
was found that the lactone underwent ring opening-epimerization
on treatment with NaOMe in MeOH at 60 ◦C, providing the
hydroxy ester in a modest 35% yield, with 55% recovered starting
material.7 Although both ring opening/epimerization reactions,
require further optimization, access to the spiro fused core of
palau’amine and related compounds has been developed. In
addition, the cycloadducts 21a–b provide an entry to the ageliferin
and potentially the related nagelamide family26 of natural products
by suitable adjustments of the stereochemistry, and these efforts
are underway.
In summary, we have developed a concise entry into the all
trans-substituted spiro cyclopentyl imidazolone system found
in palau’amine and related natural products via an IMDA
reaction of an enyne followed by an oxidative rearrangement.
Initial experiments aimed at elaborating this intermediate have
demonstrated that precursors suitable for investigating various
end-game strategies can be constructed by differentiating the two
one-carbon sidechains. Currently we are investigating methods for
the stereoselective incorporation of the chloro moiety, and for the
construction of the remaining rings.
Scheme 3
§
Acknowledgements
have prepared a large number of cycloadducts related to 21a–b,
with the exception that they are all trans substituted, and in these
cases the corresponding coupling constants are substantially larger
J4a,7a = 12.8–13.6 Hz, and J7a,8 = 10.1–10.8 Hz.11 Further, in
several cases the relative configurations of these derivatives have
been rigorously established by X-ray crystallography. We have
found that the reduction product undergoes ring opening with
epimerization at the center adjacent to the ester providing the
all trans diastereomer 24 in 51% yield (35% recovered starting
materials). This product now possesses the correct stereochemistry
for use in an approach to the ageliferin family of natural products.22
With the all-cis cycloadducts 21a–b in hand, our next task
involved its elaboration, including its rearrangement into the
spiro fused system. We have shown previously that this can
be accomplished through an oxidative rearrangement using
dimethyldioxirane,6 and while this works well in many cases,
aspects of this chemistry were unattractive, in particular the need
to prepare isolated reagent.23 It has recently been found that
this same rearrangement can be performed using Davis’ reagents
(N-sulfonyloxaziridines)24 in comparable, and in many cases, with
improved efficiencies.25 Accordingly, when 21a–b were treated with
two equivalents of Davis reagent in CHCl3 at 40 ◦C, it undergoes
a smooth oxidative rearrangement providing a single spiro imida-
zolone 22a–b in good yield. The exquisite chemoselectivity for the
This work was supported by the Robert A. Welch Foundation
(Y-1362 (CJL) and Y-1289 (HVRD)) and the NIH (GM065503).
The NSF (CHE-9601771, CHE-0234811) is thanked for partial
funding of the purchases of the NMR spectrometers used in this
work.
Notes and references
§ Compounds 20a–b, 21a–b, 22a–b, 23 and 24 were prepared as racemic
mixtures, of which one enantiomer is depicted in Scheme 3 and in the
Figures S1 and S2 illustrating the X-ray crystal structures (ESI section).
¶ X-Ray data for compound 22a: Chemical formula, C26H24N4O3; FW,
˚
440.49; Monoclinic, Space group = P21/n; a = 11.5704(8) (A), b =
14.5997(10), c = 12.5793(9), a = 90◦, b = 95.664(1)◦, g = 90◦; V =
3
˚
2114.6(3) A ; Z = 4; Mo Ka radiation, Temp. = 100(2) K; reflections, 4144
independent (Rint = 0.0272); R1 and wR2 (I = 2s(I)) = 0.0338, 0.1009; R1
and wR2 (all data) = 0.0448, 0.1066.
X-Ray data for compound 22b: Chemical formula, C21H23N5O5S; FW,
˚
457.50; Monoclinic, Space group = P21/n; a = 10.6504(12) (A), b =
19.300(2), c = 11.4094(13), a = 90◦, b = 115.389(2)◦, g = 90◦; V =
3
˚
2118.7(4) A ; Z = 4; Mo Ka radiation, Temp. = 100(2) K; reflections, 5092
independent (Rint = 0.0794); R1 and wR2 (I = 2s(I)) = 0.0508, 0.1380; R1
and wR2 (all data) = 0.0628, 0.1468.
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