Novel Oxidative Transformation of Indenoisoquinolines to Isoquinoline-3-spiro-3′-phthalides in the Presence of Osmium Tetraoxide and 4-Methylmorpholine N-Oxide

Full text of DOI:10.1021/jo980928y

5736
J . Org. Chem. 1998, 63, 5736-5737
Sch em e 1a
Novel Oxid a tive Tr a n sfor m a tion of
In d en oisoqu in olin es to
Isoqu in olin e-3-sp ir o-3′-p h th a lid es in th e
P r esen ce of Osm iu m Tetr a oxid e a n d
4-Meth ylm or p h olin e N-Oxid e
Muthusamy J ayaraman,† Phillip E. Fanwick,‡ and
Mark Cushman*,†
Department of Medicinal Chemistry and Molecular
Pharmacology, School of Pharmacy and Pharmacal Sciences,
and Department of Chemistry, Purdue University,
West Lafayette, Indiana 47907
Received May 19, 1998
Osmium-mediated dihydroxylation of olefins has proven
to be extremely valuable in organic synthesis.1 Although
the use of stoichiometric osmium presents major drawbacks
in terms of both toxicity and cost, the Sharpless asymmetric
dihydroxylation reaction permits enantioselective reactions
utilizing catalytic amounts of osmium and has been utilized
extensively in various total syntheses.2,3 In the case of
catalytic dihydroxylation, the catalytic cycle may be viewed
in three stages: (1) osmylation, i.e., alkene oxidation by
OsVIII; (2) hydrolysis of the OsVI osmate ester; and (3)
reoxidation of osmium by a terminal oxidant. The “Upjohn
procedure” employing 4-methylmorpholine N-oxide (NMO)
has widely been used for step 3.4 Despite the wide utility
of these reactions and extensive research, the mechanism
of this reaction is still obscure and a matter of debate.5,6
In the course of our work on the synthesis of analogues
of indenoisoquinolines,7 which were identified as highly
cytotoxic topoisomerase I inhibitors and are currently under
biological evaluation,8 we attempted the osmium-catalyzed
dihydroxylation of the double bond of the allyl group in the
indenoisoquinoline 4a (Scheme 1). Osmium tetraoxide (2
drops, 2.5% solution in t-BuOH) was added at 0 °C to a
solution of the allyl compound 4a (1 mmol) and NMO (2
mmol) in CH2Cl2/t-BuOH/H2O (5 mL/13 mL/10 mL), and the
reaction mixture was stirred overnight. After column
purification, a less polar compound than the starting mate-
a
Reagents and conditions: (a) CHCl3, rt (30 min); (b) Eaton’s
reagent, rt (6-12 h); (c) OsO4, NMO, t-BuOH, H2O, 0-23 °C (10 h).
indenoisoquinolines 4b-e afforded isoquinoline-3-spiro-3′-
phthalides 5b-e. The structure of 5b was confirmed by a
single-crystal X-ray diffraction analysis.
In all of the reactions, the starting indenoisoquinolines
4a -e were completely consumed. The yields of the iso-
quinoline-3-spiro-3′-phthalides isolated after column chro-
matography were 5a (60%), 5b (92%), 5c (88%), 5d (81%),
and 5e (92%). In each case, minor amounts of a polar
coproduct were detected in addition to the isoquinoline-3-
spiro-3′-phthalides. When the indenoisoquinolines 4b and
4c were subjected to the reaction conditions at room tem-
perature instead of at 0 °C, the polar coproducts formed in
greater amounts. The structures 6b and 6c were assigned
to these more polar products on the basis of the spectral and
the analytical data. The assigned structure 6b was further
confirmed by single-crystal X-ray diffraction analysis. In the
case of 4b, the products 5b and 6b were obtained in a ratio
of 7:3, respectively, in 95% total yield. In the case of 4c,
the ratio of 5c to 6c was found to be 68:32, respectively. In
general, it was found that the relative amounts of the
hydroxylation products 6 could be increased by adding more
dichloromethane to the reaction mixtures.
1
rial was isolated in 60% yield. Unexpectedly, the H NMR
spectrum of the product revealed an intact N-allyl group and
the disappearance of the two methine protons that had been
present at C-12 and C-13 in the starting material. The IR
spectrum of the product displayed a strong carbonyl absorp-
tion at 1776 cm-1 as well as two other bands at 1689 and
1657 cm-1 that were assumed to indicate the presence of
two additional carbonyl groups. On the basis of analytical
and spectral data, the product was assigned the spirolactone
structure 5a (Scheme 1). Under similar conditions, the
† Department of Medicinal Chemistry and Molecular Pharmacology.
‡ Department of Chemistry.
(1) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483-2547.
(2) J acobsen, E. N.; Marko, I.; France, M. B.; Svendsen, J . S.; Sharpless,
K. B. J . Am. Chem. Soc. 1989, 111, 737-739.
(3) Kolb, H. C.; Andersson, P. G.; Sharpless, K. B. J . Am. Chem. Soc.
1994, 116, 1278-1291.
(4) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973-1976.
(5) Nelson, D. W.; Gypser, A.; Ho, P. T.; Kolb, H. C.; Kondo, T.; Kwong,
H.-L.; McGrath, D. V.; Rubin, A. E.; Norrby, P.-O.; Gable, K. P.; Sharpless,
K. B. J . Am. Chem. Soc. 1997, 119, 1840-1858.
(6) DelMonte, A. J .; Haller, J .; Houk, K. N.; Sharpless, K. B.; Singleton,
D. A.; Strassner, T.; Thomas, A. A. J . Am. Chem. Soc. 1997, 119, 9907-
9908.
(7) Cushman, M.; Cheng, L. J . Org. Chem. 1978, 43, 3781-3783.
(8) Kohlhagen, G.; Paull, K.; Cushman, M.; Nagafuji, P.; Pommier, Y.
Mol. Pharmacol., in press.
S0022-3263(98)00928-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/29/1998

Communications
J . Org. Chem., Vol. 63, No. 17, 1998 5737
The hydroxylated products 6b and 6c were subjected to
the reaction conditions in order to investigate the possible
roles of the C-12 hydroxylated indenoisoquinolines as inter-
mediates in the transformation of 4 to 5. The results showed
clearly that 6b and 6c were not converted to 5b and 5c. In
addition, it was determined that the reaction does not take
place in the absence of osmium tetraoxide and that treat-
ment of the indenoisoquinoline 4 with 1 equiv of osmium
tetraoxide without NMO also does not effect any reaction.
Hypothetical intermediates 7b and 7e were obtained by
thionyl chloride oxidation of 4b and 4e.7 Both 7b and 7e
were recovered unchanged even after subjection to the
osmium tetraoxide-NMO reaction conditions for 2 days,
indicating that they could not possibly be intermediates in
the conversion of indenoisoquinolines 4 to isoquinoline-3-
spiro-3′-phthalides 5.
In conclusion, the transformation of indenoisoquinolines
4 to isoquinoline-3-spiro-3′-phthalides 5 is unusual and
cannot be rationalized easily by “traditional” alkene osmy-
lation chemistry. Further studies are currently underway
to probe the scope and mechanism of this novel oxidative
transformation.
Ack n ow led gm en t. This research was made possible
by NIH Contract NO1-CM-67260.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and spectroscopic data for all compounds, as well as ORTEP
drawings and X-ray data in support of structures 5b and 6b (42
pages).
J O980928Y