Discovery of hypoiodite-mediated aminyl radical cyclization lacking a nitrogen radical-stabilizing group: Application to synthesis of an oxazaspiroketal-containing cephalostatin analog

Article abstract of DOI:10.1021/ol2017033

Synthesis of an oxazaspiroketal-containing bissteroidal pyrazine is described. The key transformation of this synthesis involves stereoselective formation of oxazaspiroketal via aminyl-radical cyclization of primary amine lacking a radical-stabilizing gro

Full text of DOI:10.1021/ol2017033

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4766–4769
Discovery of Hypoiodite-Mediated
Aminyl Radical Cyclization Lacking
a Nitrogen Radical-Stabilizing Group:
Application to Synthesis of an
Oxazaspiroketal-Containing
Cephalostatin Analog
Myong Koag and Seongmin Lee*
The Division of Medicinal Chemistry, College of Pharmacy, University of Texas at
Austin, Texas 78712, United States
SeongminLee@mail.utexas.edu
Received June 24, 2011
ABSTRACT
Synthesis of an oxazaspiroketal-containing bissteroidal pyrazine is described. The key transformation of this synthesis involves stereoselective
ꢀ
formation of oxazaspiroketal via aminyl-radical cyclization of primary amine lacking a radical-stabilizing group by Suarez hypoiodite oxidation.
The cephalostatin/ritterazine1 family is composed of 45
members of antineoplastic bissteroidal-pyrazine natural
products, many of them (e.g., cephalostatin 1 1) displaying
extreme antiproliferative activities with nanomolar cyto-
toxicity against the NCI 60-cancer cell line panel.2
Currently, the mode of action of these anticancer agents
is largely unknown. The fingerprint of cephalostatin bioac-
tivities in the 60-tumor panel is quite different from those
of known antitumor agents, potentially indicating a new
mode of action. Semiempirical calculations3 for rationaliz-
ing the SAR of natural cephalostatins/ritterazines and
their analogues4 show a strong correlation between bioac-
tivity and enthalpy of oxacarbenium ion formation, im-
plicating a potential role for the cephalostatins’ spiroketal
(1) (a) Pettit, G. R.; Inoue, M.; Herald, D. L.; Krupa, T. S. J. Am.
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(2) Full NCI-60 results for cephalostatins 1À9 (NSC# 363979À81,
378727À36) are on the Web at http://dtp.nci.nih.gov.
(3) LaCour, T. G. Ph.D. Thesis, Purdue University, 2001.
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Soc. 1995, 117, 10157. (b) Guo, C.; Bhandaru, S.; Fuchs, P. L.; Boyd,
M. R. J. Am. Chem. Soc. 1996, 118, 10672. (c) LaCour, T. G.; Guo, C.;
Bhandaru, S.; Boyd, M. R.; Fuchs, P. L. J. Am. Chem. Soc. 1998, 120,
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r
10.1021/ol2017033
Published on Web 08/12/2011
2011 American Chemical Society

understood. Solasodine, the aglycon of solamargine 3,
has shown significant antitumor and DNA alkylating
activities, and N-acetylation of oxazaspiro moiety in
solasodine led to loss of bioactivity,6 implying a role
for solamargine’s oxazaspiro moiety as a latent pre-
cursor of spiroaminal-derived iminium ion 4. In our
continuing efforts to discover potent cephalostatin
analogues,7 we wanted to prepare steroidal pyrazins
bearing both oxazaspiro and dioxospiro moieties.
Syntheses of solamargine-related compounds were
accomplished using steroidal cyclic enolethers8 and
hemiacetal,9 but oxazaspiroketal-containing bisteroi-
dal pyrazine has not been reported. Herein, we report
the first synthesis of an oxazaspiroketal-containing
cephalostatin analog, where aminyl radical cycliza-
tion of primary amine lacking a radical-stabilizing
group is employed as a key reaction.
Our synthesis of cephalostatin analog 5 started with the
conversion of readily available hecogenin acetate 6 into
C12 benzoate 7 via Luche reduction of C12 ketone fol-
lowed by benzoylation of the corresponding C12 alcohol.
The action of triethylsilane and borontrifluoride-etherate
on the spiroketal 7 opened the F-ring stereoselectively to
give a primary alcohol 8, which was then converted into
steroidal azide 9 by mesylation followed by azide forma-
tion. The Staudinger reduction of azide 9 produced a
primary amine 10, which set the stage for a crucial aminyl
radical cyclization (Scheme 1).
Scheme 1. Synthesis of Steroidal Oxazaspiroketal 10
Figure 1. Steroidal alkaloids. Cephalostatin 1 (1) and solamar-
gine (2) as potential alkylating agents.
moiety as a latent precursor of oxacarbenium ion (e.g.,
E-ring oxacarbenium ion 2), which can react with bio-
nucleophiles (e.g., DNA) to exert their bioactivities
(Figure 1). Solamargine5 3 is a steroidal alkaloid
glucoside that has shown to be highly effective at
treating skin cancers with exceptional selectivity.
The mechanism of action of solamargine 3 is poorly
(5) (a) Cham, B. E.; Daunter, B. Cancer Lett. 1990, 55, 221. (b) Cham,
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With a primary alkyl amine 10 in hand, we explored
formation of 5/6 oxazaspiroketal 11 via intramolecular
Org. Lett., Vol. 13, No. 18, 2011
4767

hydrogen abstraction of a nitrogen-centered radical. When
steroidal alkyl amine 10, which does not have a radical-
to our study was establishment of 5/6 and 5/5 spiro
moieties using an amide.12 Therefore, our cyclization
reaction would be among the first, if not the first,
example of hypoiodite-mediated aminyl radical cycli-
zation that does not utilize nitrogen radical stabiliza-
tion. The THF moiety, which can stabilize carbon
radical generated by transposition of nitrogen radical,
appears to play a crucial role in the cyclization of
nonstabilized nitrogen radical. Indeed, alkyl amines,
such as octyl amine and isoamyl amine, that do not
have carbon-radical stabilizing moiety did not undergo
cyclization. This suggests that when a carbon radical-
stabilizing group is positioned properly, hypoiodite-
mediated radical cyclization can occur without amine
modification, which is often cumbersome to install and
remove.
Our attempts to capture or monitor reaction inter-
mediates of the cyclization failed. A potential reac-
tion mechanism for radical cyclization of primary
amine 10 is shown in Figure 2. Action of iodobenzene
diacetate and iodine on alkyl amine 10 produces
N-iodoamine 12, which generates nitrogen-centered
radical 13. 1,6-Transposition of the radical center from
nitrogen to carbon by intramolecular hydrogen ab-
straction gives a carbon radical 14, which is stabilized
by adjacent oxygen atom through resonance. The
carbon radical 14 reacts with iodine radical to form
iodocyclic ether 15. Oxygen atom-assisted removal
of iodide produces oxacarbenium ion 16, which is
then quenched by the adjacent amine group to afford
oxazaspiroketal 11.
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stabilizing group, was subjected to Suarez hypoiodite
oxidation10 in the presence of iodobenzene diacetate and
iodine, aminyl radical cyclization occurred smoothly (0 °C,
10 min, 90%) to afford the desired cyclization product
11 in a regio- and stereoselective fashion. Such a facile
cyclization was quite surprising because hypoiodite-
mediated aminyl radical cyclizations typically involve
nitrogen radical-stabilizing groups,11 such as cyana-
mide, amide, nitroamine, phosphoro amidate, and
sulfonamide groups, to make the radicals more reac-
tive toward hydrogen abstraction. The closest example
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Having successfully prepared steroidal oxazaspiro-
ketal 11, we next investigated synthesis of bissteroidal
pyrazine 21. Removal of the C3 acetate group of
(10) (a) Meystre, C.; Heusler, K.; Kalvoda, J.; Wieland, P.; Anner,
G.; Wettstein, A. Helv. Chim. Acta 1962, 45, 1317. (b) Danishefsky, S. J.;
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Figure 2. Proposed mechanism for oxazasprioketal formation
via aminyl radical cyclization of alkylamine 10.
4768
Org. Lett., Vol. 13, No. 18, 2011

91% yield. Installation of bromine in the C2 position
of ketone 17 turned out to be problematic. Bromina-
tion trials with phenyltrimethyl ammonium tribromide
(PTAB) and other brominating agents generated
mixtures of multiple unknown compounds. After
many experiments, we found that protection of the
secondary amine with hydrochloride prior to PTAB
addition solved a such problem and provided R bro-
moketone 18, which was then treated with tetramethyl-
guanidium azide (TMGN3) to give R azidoketone 19 in
63% over two steps. Lastly, under the conditions of
the Guo-Fuchs unsymmetrical pyrazine coupling,13
azidoketone 19 reacted smoothly with an amino-
methoxime 20 prepared also from hecogenin acetate
to yield the target bis-steroidal pyrazine 5 in 76% yield
(Scheme 2).
Scheme 2. Synthesis of Bissteroidal Pyrazine 5
In summary, our synthesis of oxazaspiroketal-con-
taining steroidal pyrazine was accomplished in 12 steps
and 28% overall yield starting from hecogenin acetate,
where aminyl radical cyclization of primary amine
established the requisite oxazasprioketal moiety. Cur-
ꢀ
rently, we are applying this modified Suarez cyclization
to other substrates with functional groups that can
stabilize transposed carbon radicals, and the results
will be reported in due course.
Acknowledgment. The research was supported by the
Robert A. Welch Foundation (Grant No. F-1741). We are
~
grateful to Begona Stevenson (Department of Chemistry
and Biochemistry, The University of Texas at Austin),
Charisse Crenshaw (Salk Institute), and Daniel Jamieson
(Department of Chemistry, Purdue University) for helping
with the manuscript preparation.
Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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oxazaspiroketal 11 followed by peruthenate oxidation
of the corresponding alcohol produced C3 ketone 17 in
Org. Lett., Vol. 13, No. 18, 2011
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