Diastereoselective synthesis of cyclopentapyridazinones via radical cyclization: Synthetic studies toward halichlorine

Article abstract of DOI:10.1021/ol801849u

(Equation Presented) The pyridazinone ring system serves as an excellent scaffold for the diastereoselective preparation of novel cis-fused cyclopentapyridazinones utilizing the directed 5-exo radical cyclization approach. This overall approach was succes

Full text of DOI:10.1021/ol801849u

ORGANIC
LETTERS
2008
Vol. 10, No. 21
4783-4786
Diastereoselective Synthesis of Cyclopenta-
pyridazinones via Radical Cyclization:
Synthetic Studies Toward Halichlorine
Gary E. Keck* and Stacey A. Heumann
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM 2020,
Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received August 8, 2008
ABSTRACT
The pyridazinone ring system serves as an excellent scaffold for the diastereoselective preparation of novel cis-fused cyclopentapyridazinones utilizing the
directed 5-exo radical cyclization approach. This overall approach was successfully employed in the preparation of a functionalized aza-spirocycle.
Intramolecular radical additions offer a powerful means for
constructing both carbo- and heterocyclic ring systems.1
Scheme 1. Formation of Cyclopentapyridazinone
There are numerous examples employing alkenes and alkynes
as radical acceptors for ring formation,2 and over the past
decade, interest in imine-like1d,3 acceptors for radical cy-
clization reactions has steadily grown. Specifically, among
these examples, the formation of cyclic structures using
exocyclic imine-like acceptors has ample precedent.1d,3e,4
However the formation of fused ring systems using cyclic
hydrazone acceptors as part of both stereodefining and
directing templates has been virtually unexplored.
embedded hydrazone could function as a radical acceptor, and
the ring’s inherent rigidity could provide for the diastereose-
In our pursuit to develop general methods for the synthesis
of structural motifs found in biologically relevant molecules,
pyridazinones appeared to be promising candidates for the
synthesis of synthetically useful fused bicycles (Scheme 1). The
(3) For examples of hydrazone acceptors, see: (a) Sturino, C. F.; Fallis,
A. G. J. Am. Chem. Soc. 1994, 116, 7447. (b) Marco-Contelles, J.; Balme,
G.; Bouyssi, D.; Destabel, C.; Henriet-Bernard, C. D.; Grimaldi, J.; Hatem,
J. M. J. Org. Chem. 1997, 62, 1202. (c) Tauh, P.; Fallis, A. G. J. Org.
Chem. 1999, 64, 6960. (d) Friestad, G. K.; Fioroni, G. M. Org. Lett. 2005,
7, 2393For examples of imine acceptors, see: (e) Tomaszewski, M. J.;
Warkentin, J. Chem. Commun. 1993, 966. (f) Bowman, W. R.; Stephenson,
P. T.; Terrett, N. K.; Young, A. R. Tetrahedron Lett. 1994, 35, 6369. (g)
Kim, S.; Yoon, K. S.; Kim, Y. S. Tetrahedron 1997, 53, 73. For examples
of N-aziridinylimine acceptors, see: (h) Kim, S.; Kee, I. S.; Lee, S. J. Am.
Chem. Soc. 1991, 113, 9882. (i) Lee, H.-Y.; Kim, D-I.; Kim, S. Chem.
Commun. 1996, 1539For examples of oxime acceptors, see: (j) Keck, G. E.;
Wager, T. T. J. Org. Chem. 1996, 61, 8366. (k) Miyata, O.; Muroya, K.;
Koide, J.; Naito, T. Synlett 1998, 271. (l) Keck, G. E.; Wager, T. T.;
Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176. (m) Clive, D. L. J.;
Pham, M. P.; Subedi, R. J. Am. Chem. Soc. 2007, 129, 2713.
(1) (a) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. ReV. 1991, 91,
1237. (b) Marco-Contelles, J.; Ruiz, P.; Sanchez, B.; Jimeno, M. L.
Tetrahedron Lett. 1992, 33, 5261. (c) Curran, D. P.; Sisko, J.; Yeske, P. E.;
Liu, H. Pure Appl. Chem. 1993, 65, 1153. (d) Keck, G. E.; Wager, T. T.;
McHardy, S. F. J. Org. Chem. 1998, 63, 9164.
(2) (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.; Okawara, M.
J. Am. Chem. Soc. 1982, 104, 5564. (b) Stork, G.; Mook, R.; Biller, S. A.;
Rychnovsky, S. D. J. Am. Chem. Soc. 1983, 105, 3741. (c) Choi, J.-K.;
Hart, D. J. Tetrahedron 1985, 41, 3959. (d) Fukuzawa, S.-i; Tsuchimoto,
T. Synlett 1993, 803. (e) Miyata, O.; Nishiguchi, A.; Ninomiya, I.; Aoe,
K.; Okamura, K.; Naito, T. J. Org. Chem. 2000, 65, 6922.
10.1021/ol801849u CCC: $40.75
Published on Web 09/25/2008
2008 American Chemical Society

lective installation of the fused cyclopentane via a facile 5-exo
radical cyclization. In addition, it was our intent to explore this
radical reaction’s potential to provide a key intermediate for use
in efforts directed at the synthesis of the natural product halichlorine.
The chiral pyridazinone was easily accessed in five steps
starting with 4-pentenoic acid 1 (Scheme 2). Initial amide
Scheme 3. 5-Exo Radical Cyclization
Scheme 2. Synthesis of Functionalized Pyridazinones
pyridazinones 5 and 6 provided cyclopentapyridazinones 7
and 8 in good yield upon exposure to HSnBu3 and azo-
biscyclohexylnitrile (ACN) in toluene at reflux. As expected,
the cis-fused bicycles were the only detectable diastereomers
formed in the reaction. Thus, the initial pyridazinone scaffold
provides the necessary rigidity for efficient transfer of
stereochemical information during the 5-exo radical cycliza-
tion. This addition thus leads to the generation of a new
stereogenic center bearing a masked amino group.
In light of these successful radical cyclizations, we decided
to explore this new method in a strategy directed at the
synthesis of the biologically relevant natural product hali-
chlorine. Specifically, we hoped to exploit this powerful
method as the initial stereochemistry-defining reaction in the
generation of the aza-spirocyclic core of halichlorine.
Halichlorine 99 is an alkaloid that was isolated from the
marine sponge Halichondria okadai Kadota in 1996 by Uemura
and co-workers (Scheme 4).10 The 15-membered macrolide has
been shown to significantly inhibit the expression of VCAM-1
(vascular cell adhesion molecule). VCAM-1 is involved in
promoting and regulating leukocyte uptake into inflamed tissue.
Inhibition of this process is relevant to a variety of disease states,
including asthma, atherosclerosis, coronary artery diseases, and
noncardiovascular inflammatory diseases.10,11
coupling with (1R,2R)-(-)-pseudoephedrine was followed
by the Myers’ diastereoselective alkylation protocol5 using
1-chloro-3-iodo-propane. The auxiliary was subsequently
removed with n-BuLi providing chiral ketone 2.6 The
terminal olefin in ketone 2 was then cleaved to give γ-keto
acid 3. Initial attempts to transform this substrate into the
corresponding oxazinone 4 under a variety of conditions were
fruitless.7 However, we were delighted to find that treatment
of carboxylic acid 3 with hydrazine hydrate produced
pyridazinone 5 in high yield and that the use of methyl
hydrazine led to N-methyl pyridazinone 6.7,8 It is important
to recognize that oxazinone 4, pyridazinone 5, and N-methyl
pyridazinone 6 represent essentially equivalent substrates for
our purposes; both oxime ethers and hydrazones have been
shown to perform well as radical acceptors.3
Retrosynthetically, halichlorine 9 can be dissected through
a hydrolysis of the C1-C21 lactone followed by a discon-
nection of the C15-C16 olefin giving rise to the halichlorine
spiroquinolizidine core 10 as well as Z-vinyl chloride 11
(Scheme 4). The core 10 can then be simplified by extrusion
In preparation for the radical cyclization, the chlorides in
compounds 5 and 6 were exchanged for iodides using
Finkelstein conditions (Scheme 3). To our delight, both
(8) (a) Cignarella, G.; Barlocco, D.; Pinna, G. A.; Loriga, M.; Curzu,
M. M.; Tofanetti, O.; Germini, M.; Cazzulani, P.; Cavalletti, E. J. Med.
Chem. 1989, 32, 2277. (b) Combs, D. W.; Rampulla, M. S.; Demers, J. P.;
Falotico, R.; Moore, J. B. J. Med. Chem. 1992, 35, 172. (c) Stajer, G.;
Szabo, A.; Bernath, G.; Sohar, P. Heterocycles 1994, 38, 1061.
(4) (a) Parker, K. A.; Spero, D. M.; Van Epp, J. J. Org. Chem. 1988, 53,
4628. (b) Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Chem. Lett.
1990, 315. (c) Booth, S. E.; Jenkins, P. R.; Swain, C. J.; Sweeney, J. B. J.
Chem. Soc., Perkin Trans. 1 1994, 3499. (d) Clive, D. L. J.; Zhang, J.; Subedi,
R.; Bouetard, V.; Hiebert, S.; Ewanuk, R. J. Org. Chem. 2001, 66, 1233.
(5) (a) Myers, A. G.; Yang, B. G.; Chen, H.; Gleason, J. L. J. Am. Chem.
Soc. 1994, 116, 9361. (b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry,
L.; Kopecky, D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(6) During our initial studies, the enantiomer of the compounds shown
in Schemes 2, 3, 5, and 6 was used. For simplicity, only one enantiomer is
consistently shown throughout all schemes.
(7) (a) El Hashash, M. A.; El Kady, M. Y.; Mohamed, M. M. Ind.
J. Chem. Sect. B: Org. Chem. Incl. Med. Chem. 1979, 18, 136. (b) Best,
W. M.; Brown, R. F. C.; Tiso, P. D.; Watson, K. G. Aust. J. Chem. 1990,
43, 427. (c) Essawy, S. A. Ind. J. Chem. Sect. B: Org. Chem. Incl. Med.
Chem. 1991, 30, 371.
(9) For total syntheses of halichlorine, see: (a) Trauner, D.; Schwarz,
J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1999, 38, 3542. (b) Christie,
H. S.; Heathcock, C. H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12079.
For a comprehensive review of synthetic approaches, see: (c) Clive, D. L. J.;
Yu, M.; Wang, J.; Yeh, V. S. C.; Kang, S. Chem. ReV. 2005, 105, 4483.
For recent synthetic approaches not covered in ref 9c, see: (d) Andrade,
R. B.; Martin, S. F. Org. Lett. 2005, 7, 5733. (e) Kim, H.; Seo, J. H.; Shin,
K. J.; Kim, D. J.; Kim, D. Heterocycles 2006, 70, 143. (f) Sinclair, A.;
Arini, L. G.; Rejzek, M.; Szeto, P.; Stockman, R. A. Synlett 2006, 14, 2321.
(g) Hurley, P. B.; Dake, G. R. J. Org. Chem. 2008, 73, 4231.
(10) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3867.
4784
Org. Lett., Vol. 10, No. 21, 2008

alkylation of compound 19 with methyl iodide which
afforded compound 20 in 94% yield and as a single
diastereomer.12 The chloride in compound 20 was exchanged
for an iodide, and as expected, cyclopentapyridazinone 21
was formed upon exposure to HSnBu3 and ACN in toluene
at reflux, in 86% yield over the two-step sequence.
Scheme 4. Retrosynthetic Analysis of Halichlorine 9
Elaboration to a simplified aza-spirocycle was next
explored (Scheme 6). Initially the N-N bond cleavage was
Scheme 6. Formation of Aza-Spirocycle via Mitsunobu
of the C1,C2,C22 segment 12 to unveil the aza-spirocycle 13.
The spirocycle 13 was envisioned to arise through an SN2
displacement using a N-N bond-cleaved derivative of
cyclopentapyridazinone 14. This intermediate could be
constructed stereoselectively using the 5-exo radical cycliza-
tion approach from pyridazinone 15.
To access the pyridazinone with the desired substitution
in place, the alkylated pseudoephedrine analogue 16 was
treated with the alkyl lithium reagent derived from alkyl
iodide 17 (Scheme 5). The olefin in the resulting ketone 18
attempted using dissolving metal conditions. Interestingly, while
cyclopentapyridazinone 21 was fully consumed, only 15% of
cis-fused cyclopentalactam 22 was isolated; none of the desired
uncyclized compound was observed. This unexpected result
prompted us to use alternative conditions. After acylation of
the amine nitrogen, the N-N bond was reductively cleaved
using SmI2 to give the ring-opened trifluoroacetamide 23.13 The
TBS group was then removed, and the primary alcohol 24 was
treated under Mitsunobu conditions, which afforded the target
aza-spirocycle 25 in 69% yield.
Scheme 5. Installation of C14 Methyl and C9-C13 Cyclopentane
The initial stereocenter obtained through Myers’ alkylation,
coupled with the rigidity of the pyridazinone radical accepter,
ultimately provided access to three of the four stereocenters
found in halichlorine. We envisioned that the remote C5
stereocenter of the aza-spirocycle found in the natural product
might be accessed using the catalytic asymmetric allylation
(CAA) reaction.14 Toward this end, the C5 silyl ether 20 was
converted into aldehyde 26 by removal of the TBS group
followed by Swern oxidation (Scheme 7). Aldehyde 26 was
(11) (a) Bevilacqua, M. P.; Nelson, R. M.; Mannori, G.; Cecconi, O.
Annu. ReV. Med. 1994, 45, 361. (b) Carlos, T. M.; Harlan, J. M. Blood
1994, 84, 2068. (c) Foster, C. A. J. Allergy Clin. Immunol. 1996, 98, S270.
(d) Yusuf-Makagiansar, H.; Anderson, M. E.; Yakovleva, T. V.; Murray,
J. S.; Siahaan, T. J. Med. Res. ReV. 2002, 22, 146.
(12) The more obvious sequence of alkylation after radical cyclization
was found to give much lower levels of diastereoselectivity for introduction
of the methyl group (ca. 2:1).
(13) (a) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637. (b) Friestad,
G. K.; Marie, J.-C.; Deveau, A. M. Org. Lett. 2004, 6, 3249.
(14) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc. 1993,
115, 8467. (b) Keck, G. E.; Krishnamurthy, D. Org. Synth. 1998, 75, 12.
was oxidatively cleaved with NaIO4 and catalytic KMnO4
to give the carboxylic acid that was then condensed with
methyl hydrazine to provide the “N-methyl protected”
pyridazinone 19. This was then followed by a rather daring
Org. Lett., Vol. 10, No. 21, 2008
4785

explored the potential of cleaving the N-N bond in 29 using
dissolving metal conditions with sodium in place of lithium.
Use of sodium in ammonia provided the bicyclic lactam 30
in 72% yield (Scheme 9). It should be recognized that the
Scheme 7. CAA and 5-Exo Radical Cyclization
Scheme 9. Approach to Halichlorine’s Aza-Spirocycle
then treated under the CAA conditions using R-BINOL. This
reaction gave alcohol 27 in an excellent 85% yield as only one
detectable diastereomer. In addition, aldehyde 26 was converted
to the C5 epimeric alcohol epi-27 using S-BINOL under
otherwise identical conditions; this ultimately proved important
for establishing the relative and absolute configurations in this
series.
The pyridazinone 27was then treated under the radical
cyclization conditions to give cis-fused cyclopentapyridazinone
28 in 85% yield (Scheme 7). Similarly the pyridazinone epi-
27 was treated under these radical cyclization conditions and
yielded cyclopentapyridazinone epi-28. Assignment of the
relative and absolute configuration of our compounds was
verified by X-ray analysis of compound epi-28 (Scheme 8).
cyclopentalactams 22 and 30 could also serve as potential
intermediates for accessing halichlorine.15
Acylation of 29 with TFAA followed by treatment with
SmI2 afforded the ring opened product 31 (Scheme 9). The
TBS group was removed, and alcohol 32 was treated under
Mitsunobu conditions. Unfortunately, all attempts to cause
the SN2 displacement of the C5 alcohol and its derivatives
to give the aza-spirocycle 33 were futile; elimination products
were formed predominately.
In summary, the pyridazinone ring system has served as an
excellent scaffold for preparing novel cis-fused cyclopentapy-
ridazinones utilizing the directed 5-exo radical cyclization
approach discussed above. This strategy to access compounds
like 7, 8, 21, and 28 presents a direct, diastereoselective method
to access these substructures that contain a new quaternary
stereocenter in essentially enantiomerically pure form.
In the context of an approach to halichlorine, the rigid
pyridazinone ring system led to the facile and highly
diastereoselective installation of the cis-C9-C13 cyclopentane
ring as well as the C14 methyl found in halichlorine. The
CAA reaction provided a highly stereoselective method to
generate the remote hydroxy stereocenter that was slated to
provide the C5-N bond of the aza-spirocycle. However, the
ring closure from this intermediate will require further study.
Scheme 8. Synthesis and ORTEP Representation of epi-28
Acknowledgment. Financial assistance provided by the
NIH (through grant GM29861) is gratefully acknowledged.
Supporting Information Available: Full experimental
details as well as spectral and characterization data for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL801849U
Finally, we have examined application of this methodology
to the aza-spirocycle found in halichlorine. Initially, we
(15) See intermediate 6 in ref 9a.
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