Alkynyliodonium salts in organic synthesis. Application to the total synthesis of the tropoloisoquinoline alkaloid pareitropone

Article abstract of DOI:10.1021/ja0277430

The synthesis of the tropoloisoquinoline alkaloid pareitropone has been accomplished in 14 steps from 2,3,4-trimethoxybenzoic acid. The key transformations include the generation of an alkylidenecarbene intermediate through intramolecular addition of a to

Full text of DOI:10.1021/ja0277430

Published on Web 09/04/2002
Alkynyliodonium Salts in Organic Synthesis. Application to the Total
Synthesis of the Tropoloisoquinoline Alkaloid Pareitropone
Ken S. Feldman* and Timothy D. Cutarelli
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received July 17, 2002
Scheme 1
The emergence of alkynyliodonium salts as useful reagents in
organic synthesis can be traced to their ready conversion into
reactive alkylidenecarbenes upon exposure to weakly basic polariz-
able nucleophiles.1 These monovalent carbenes are among the most
energetic organic fragments known,2 and discharge of this energy
via a variety of decomposition pathways can result in the formation
of new structural frameworks with significant increases in molecular
complexity.3 Nowhere is this paradigm more evident, perhaps, than
in the nucleophilic addition of 1-tosylamido-2,4-pentadienes to the
simple alkynyliodonium salt phenyl(propynyl)iodonium triflate to
furnish bicyclic dihydropyrrole products in a single operation.4 This
sequence involves a pivotal intramolecular cycloaddition of a
derived alkylidenecarbene to a proximal alkene that generates a
severely strained methylenecyclopropane product. The successful
utilization of an electronically unactivated olefin raises the related
question of whether an arene ring might be reactive enough to
substitute for the alkene in this transformation. Examples of
alkylidenecarbene cycloaddition to aromatic rings are scarce,5,7 but
enforced proximity of reactive entities and the availability of a low-
Scheme 2
energy decomposition pathway for the first-formed methylenecy-
clopropane may suffice to facilitate this process.
The motivation for pursuing this line of inquiry stems from
an interest in the synthesis of the tropoloisoquinoline alkaloid
pareitropone (1),6a Scheme 1. Pareitropone is the most potent
anticancer agent among the relatively small family of tropoloiso-
quinoline alkaloids, with a reported IC50 of 2.7 nM versus the P388
leukemia cell line.6a Successful syntheses (or attempts at synthesis)
of other members of this class (for example, grandirubrine,
imerubrine, isoimerubrine),6b-e which differ structurally from 1 by
the position and extent of oxygenation, have been reported,8 but
the strategies employed in those efforts do not lend themselves to
a ready solution for the particular oxygenation pattern of 1.
However, a concise approach to this target structure, which passes
through the alkynyliodonium salt 5 and alkylidenecarbene 4 en route
to the cycloheptanoid product 2, can be envisioned.8f This strategy
is not without risk, as direct 1,6 C-H insertion within carbene 4
to furnish phenanthrene product 6 cannot be dismissed, given the
similar alkylidenecarbene-based phenanthrene synthesis reported
by Harrington et al.7 and our own earlier work on this topic.9
Nevertheless, the successful implementation of this strategy has
been realized, leading to the first total synthesis of this potent
antileukemic principle.
conveniently prepared from the iodide 8a using the procedure of
Knochel et al.12 Acid-mediated hydrolysis of the oxazoline unit in
9 required assistance from the pendant alcohol, and the intermediate
lactone so formed was reduced cleanly to the diol 10. Attempts to
hydrolyze or reduce the oxazoline ring in a model system (with
OTIPS ) OCH3 in 8) lacking the alcohol unit were frustrated by
either recovery of starting material or compound destruction.13 Thus,
combination of the aryl anion derived from lateral metalation of
The assembly of the alkynylstannane cyclization precursor 12
commenced with functionalization of the known oxazoline 7,11a
Scheme 2. Fundamental advances in arene addition chemistry from
the Meyers laboratory10 were exploited for the introduction of both
the p-silyloxyaryl moiety and the ethyl alcohol fragment as shown
in the conversion of 7 into 9.11 The Grignard reagent 8b was
* To whom correspondence should be addressed. E-mail: ksf@chem.psu.edu.
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10.1021/ja0277430 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
conversion might include initial fluoride-induced elimination of the
elements of Ts-TIPS to afford an unobserved dihydropareitropone
intermediate 15. Apparently, air oxidation of 15 is facile, and the
fully aromatic isoquinoline core of 1 provides enough of a
thermodynamic sink to drive the reaction to the desired target. The
spectral data (1H NMR, 13C NMR) for synthetic pareitropone
matched those reported in the literature for the naturally derived
material.6a
In summary, the tropoloisoquinoline alkaloid pareitropone has
been synthesized for the first time in a 14-step route from
commercially available 2,3,4-trimethoxybenzoic acid (7% overall
yield). The chemistry features a rather cryptic use of alkynyliodo-
nium salts in the context of cycloheptatrienylidene synthesis from
aryl ring precursors.
Acknowledgment. We thank the National Institutes of Health
(GM37681) for financial support.
Supporting Information Available: Characterization data (1H and
13C NMR, IR, LRMS, HRMS, or elemental analysis) and copies of 1H
and 13C NMR spectra for 1, 9-12, and 14. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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(2) The heat of formation of the parent compound vinylidene (H2CdC:) can
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A. J. Am. Chem. Soc. 2001, 123, 641 and references therein.
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the oxazoline with tosylaziridine (in lieu of ethylene oxide) afforded
excellent yields of the desired ethyltosylamide appendage, but this
promising intermediate proved to be a dead end.
A more indirect approach to tosylamide introduction, which
passed through the alkynol 11, was pursued. Mitsunobu-type
displacement of the alcohol in 11 with TsNHFmoc led to the
secondary tosylamide directly, as apparently the Fmoc tosylimide
intermediate suffers decarboxyfluorenylation under the mildly basic
reaction conditions.14 Stannylation of the terminal alkyne in the
intermediate tosylamide proceeded uneventfully, delivering the
cyclization precursor 12 in moderate yield.
Exposure of this alkynylstannane 12 to Stang’s reagent (PhI-
(CN)OTf)15 at -40 °C followed by solvent removal at this
temperature resulted in formation of the iodonium salt 13 as a
yellow oily solid which decomposed upon warming to ca. 0 °C,
Scheme 3. Dissolution of this residue in DME at -40 °C preserved
the integrity of this sensitive species, and subsequent treatment with
LiNTMS2 triggered a cascade of reactions that presumably pass
through intermediates of the type illustrated in Scheme 1 to deliver
the cycloheptatrienylidene product 14 in good yield as the only
isolable material. No evidence for an alternative phenanthrene-type
product (cf. 6) could be gleaned from inspection of the crude
reaction mixture’s 1H NMR spectrum. Perhaps this alkylidenecar-
bene reaction selectivity can be attributed simply to proximity, as
a comparison of the key carbene-arene carbon and carbene-
hydrogen distances, revealed by an electronic structure calculation
on the model system 16,16 argues for reaction at the former site.
Unexpectedly, the dark blue-green tetraene 14 could be converted
to the natural product pareitropone (1) by simple treatment with
KF on Al2O3 at -78 °C with subsequent warming to ambient
temperature. A plausible sequence of events that describes this
(11) (a) Ladd, D. L.; Weinstock, J.; Wise, M.; Gessner, G. W.; Sawyer, J. L.;
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D. B. Can. J. Chem. 1983, 61, 7.
(12) Abarbri, M.; Thibonnet, J.; Be´rillon, L.; Dehmel, F.; Rottla¨nder, M.;
Knochel, P. J. Org. Chem. 2000, 65, 4618.
(13) We thank Dr. Romina Di Florio for performing these experiments. Details
will be provided in a full account of this work.
(14) Bach, T.; Kather, K. J. Org. Chem. 1996, 61, 7642.
(15) Stang, P. J.; Zhdankin, V. V. J. Am. Chem. Soc. 1991, 113, 4571.
(16) A density functional calculation using a perturbative Becke-Perdew
model, and the DN* basis set in Spartan 5.0 was employed to arrive at
the energy minimized structure 16.
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